iiHiiiiiin 



tiii' 



it 



i 



I 



n 



puno! 



Ill 
1 1 it i 



U i 



f 



I Mi 



I 



V: ! 



IBB 



" There are more mistakes made in the diagnosis of malaria 
with the microscope than perhaps over any other similar study; 
on the other hand, if properly employed, it may give valuable 
information, leading perhaps to the saving of life" (Manson). 



A PRACTICAL STUDY 



OF 



M AL 




BY 

WILLIAM H. DEADERICK, M. D. 

Member of the Arkansas Medical Society, American Medical Association, and American 

Society of Tropical Medicine; Fellow of the London Society of Tropical 

Medicine and Hygiene; Corresponding Member Societe de 

Pathologie Exotique (Paris) ; President of the 

Tri-State Medical Society 



FULLY ILLUSTRATED 



PHILADELPHIA AND LONDON 

W. B. SAUNDERS COMPANY 

1909 






Copyright, 1909, by W. B. Saunders Company 



>CI.A25;I«462 



PRINTED IN AMERICA 



PRESS OF 

W. B. SAUNDERS COMPANY 

PHILADELPHIA 



THESE PAGES ARE 

AFFECTIONATELY DEDICATED 

TO MY MOTHER 



PREFACE 



While there is a number of good books on malaria, I be- 
lieve there is a place for a work written by one engaged entirely 
in private practice largely in country districts, in the home of the 
severer forms of the disease. 

In the endeavor to make the work as practical as possible 
especial attention has been devoted to that mystic paramalarial 
syndrome, hemoglobinuric fever, and to the diagnosis and treat- 
ment of malaria. Prophylaxis has been considered in the light 
of Ross' epoch-making discovery. 

The parthenogenetic cycle of the parasite, whose significance 
was first recognized by Schaudinn, and which affords the only 
rational explanation of latency and relapse, is described for the 
first time, perhaps, in our language. 

While I have not hesitated to draw from the literature for the 
illustration of practical points, due credit is given in the reference 
portion. I am especially indebted to the works of Ewing, Dock, 
Barker, Marchiafava and Bignami, and Kelsch and Kiener for 
pathologic data. 

I am grateful to my wife for copying the manuscript and for 
assistance in reading the proof, to Mr. W. C. Seckler for the 
photographic work, and to the W. B. Saunders Co. for courtesies 
throughout the publication of the book. 

W. H. D. 

Marianna, Arkansas, October, 1909. 



CONTENTS 



CHAPTER I page 

Introduction 17 

History of Hemoglobinuric Fever 23 



CHAPTER II 

Geographic Distribution 31 

Geographic Distribution of Hemoglobinuric Fever 34 



CHAPTER III 

Etiology 38 

Dissemination of Malaria by Mosquitoes 69 

The Malaria-bearing Mosquitoes 74 

Classification of the Mosquitoes of North and Middle America . . 86 

The Parasites of Malaria 112 

Pathogenesis 129 

Etiology of Pernicious Malaria 140 

Etiology of Hemoglobinuric Fever 153 



CHAPTER IV 

Pathologic Anatomy 174 

Acute Malaria 175 

Chronic Malaria 178 

Hemoglobinuric Fever 180 



CHAPTER V 

Clinical History 184 

Acute Malaria 184 

Pernicious Malaria 203 

Hemoglobinuric Fever 216 

Complications and Sequelae 232 



CHAPTER VI 

Diagnosis 256 

Differential Diagnosis 284 

Diagnosis of Pernicious Malaria 287 

Diagnosis of Hemoglobinuric Fever 289 

13 



14 CONTENTS 

CHAPTER VII page 

Prognosis 292 



CHAPTER VIII 

Prophylaxis 302 

Measures Directed for the Destruction of Mosquitoes 305 

Measures Directed Toward the Destruction of Parasites 315 

Measures to Prevent the Access of Mosquitoes 322 

Prophylaxis of Hemoglobinuric Fever 332 



CHAPTER IX 

Treatment 334 

References 388 

Index 397 



A PRACTICAL STUDY 

OF 

MALARIA 



DEADERICK 



/ 



A PRACTICAL 

STUDY OF MALARIA 



CHAPTER I 

INTRODUCTION 

A certain dusky tropical queen was wont to say that she 
did not fear the invasion of the white man, for she had two 
mighty generals, The Fever and The Forest. 

Malaria has been one of civilization's greatest foes, both in 
time of war and in peace. Where shot and shell have slain 
their thousands, malaria has slain its tens of thousands. 
Malaria is the chieftain of the army of disease. Even Napo- 
leon acknowledged its supremacy when he wrote his minister 
of war on the occasion of the disastrous English Walcheren 
expedition : "We are rejoiced to see that the English them- 
selves are in the morasses of Zealand. Let them be kept only 
in check, and the bad air and fevers peculiar to the climate will 
soon destroy their army." It is said that the French crowed 
over the expedition "with the force of reason, the bitterness 
of sarcasm, and the playfulness of ridicule." How accurately 
Napoleon's prediction was verified is well known. 

In the tropics the man who works the soil digs his own 
grave. Gigantic commercial enterprises have been undertaken 
and then abandoned on account of the havoc wrought by this 
scourge. Only recently has it been recognized that the medical 
man must precede and prepare the way for the engineer and 
the laborer. 

But warring and canal-digging are not the only stages upon 
which the malarial tragedy is enacted. Within the family, at 

2 17 



15 THE STUDY OF MALARIA 

home, the disease appears in a varied succession of forms, 
rapidly fatal, or slowly sapping the vitality, influencing the 
birth-rate, longevity, and even the intelligence and morality 
of entire countries. 

In highly malarial regions, as the mortality increases the 
natality diminishes on account of abortions and sterility. Pre- 
mature senility is frequent and advanced age is not so com- 
monly attained. 

Malaria, leaving its subjects anemic and neurotic, is respon- 
sible for inertia, loss of will power, intemperance, and general 
mental and moral degradation. Jones, who maintains that 
malaria was a potent factor in the decline of Greece and Rome, 
concludes that "malaria made the Greek weak and inefficient; 
it turned the sturdy Roman into a bloodthirsty brute." Mon- 
falcon attributes abortion, infanticide, universal libertinism, 
drunkenness, want of religion, gross superstition, assassination, 
and other crimes to the direct influence of malaria. 

Malaria costs the South incalculable wealth. Besides loss 
through untilled acres, diminished earning capacity, loss of 
time, and death, it produces in its victims a disinclination for 
work whose influence cannot be estimated in money. A con- 
servative computation of the loss to the Southern States 
through malaria is fifty millions of dollars annually. 

The importance to the world at large of the subject of 
malaria is evidenced by the fact that two of the seven Nobel 
prizes in medicine which have been awarded have been granted 
for discoveries in malaria — to Ross in 1902, and to Laveran 
in 1907. 

The history of malaria may be traced to the age of fable. 
The story of Hercules and the Hydra is a familiar one. This 
monster dwelt in the morasses in the neighborhood of the Lake 
of Lerna, where Hercules was dispatched to destroy him. As 
each of the nine heads was struck off two new ones appeared. 
With the aid of his faithful servant, Iolaus, who burned each 
wound caused by the removed head, the beast was finally con- 
quered. Even before the birth of Christ this myth was con- 
strued to typify the reclamation of swamp lands, uninhabitable 
on account of the prevalence of malaria. Antipater wrote, 



INTRODUCTION 1 9 

"Hercules, the greatest subduer of the foggy atmosphere in 
times past, was placed among the gods for having destroyed 
the Hydra; in other words, for having reclaimed the marshy 
desert." The slaying by Apollo of the Python which arose 
from the fertile ground after the recession of the flood is simi- 
larly interpreted. 

More than one thousand years before the birth of Christ 
malarial disease is mentioned in the Orphic poems, and the 
tertian and quartan types are alluded to. In the Iliad of 
Homer and in the Wasps of Aristophanes allusions are made 
to a fever which was probably malarial. Paludism was proba- 
bly introduced into Greece from Egypt. According to GrofT 
the word AAT, which is found among the inscriptions of the 
temple of Denderah, referred to a disease, doubtless malaria, 
which recurred every year at the same season. 

Hippocrates divided malarial fevers into continuous and 
intermittent, which he subdivided into quotidian, tertian, and 
quartan. He recognized the etiologic influence of season, rains, 
and stagnant water, and the dangers of malignancy, dropsy, 
and affections of the spleen. Plato describes splenic enlarge- 
ment, and other early Greek writers undoubtedly refer to 
malaria. 

References by Roman writers to malaria are not numerous, 
the earliest being that of Plautus, who died 184 b. c. Cato 
speaks of "black bile and swollen spleen," and Cicero, Varro, 
Celsus, Livy, and others show unmistakable evidence of a 
knowledge of the disease. 

Passing over the development during the middle ages of the 
knowledge of malaria, the names of Morton, Lancisi, Syden- 
ham, and Torti appear. 

Morton, 1697, gave accurate clinic descriptions of the perni- 
cious and simple intermittent fevers, and attributed them to 
miasmatic effluvia. He was an ardent advocate of cinchona, 
whose value was at that period being hotly contested. 

Sydenham, 1723, accurately described the malarial fevers. 
The intermittent fevers he divided into spring and autumn 
fevers. He justly concluded that the intermittent and con- 
tinuous forms of malaria were due to the same cause. Syden- 



20 THE STUDY OF MALARIA 

ham ably defended cinchona, and, after clinic experiments with 
its use, formulated useful rules for its administration. 

Lancisi, 171 7, stated the etiologic relationship between 
marshy regions and malaria, and was the first to seek for a 
microscopic organism as the cause of the disease. 

Torti, 1753, wrote an exhaustive treatise upon the various 
forms of malaria. His classification of the pernicious forms 
has become classical. Numerous quotations from Torti's 
treatise are to be found even in recent works upon malaria. 

Varro, 118-29 B - c v expressed the opinion that malarial 
fever was caused by animals so minute that they could not be 
seen by the naked eye, and which enter the body with the air 
through the nose and mouth. Similar opinions were held by 
Columella, Palladius, and Vitruvius. Rasori is quoted as say- 
ing, "For many years I have held the opinion that the inter- 
mittent fevers are produced by parasites, which renew the 
paroxysm by the act of their reproduction, which occurs more 
or less rapidly according to the variety of their species." Le 
Diberder, 1869, maintained that the fever was due to the 
presence in the blood of animals which preyed upon the blood, 
and that the paroxysms depended upon reproductive acts be- 
tween which apyrexia occurred. 

Mitchel, 1849, claimed to have found in the sputa of mala- 
rial subjects fungous spores in great numbers, which he be- 
lieved to have been inspired with marsh air and to have caused 
the disease. 

Salisbury, 1866, announced the discovery in the urine and 
sweat of malarial patients of a species of alga, palmella, com- 
mon on the marshy regions along the Ohio and Mississippi 
Rivers, which he alleged to be the causative element. 

Until the true parasite of malaria was discovered the most 
widely accepted parasitic theory was that proposed in 1879 
by Klebs and Tommasi-Crudeli. These investigators found 
constantly present in the mud of the Roman marshes a short 
bacillus. They were able to cultivate it upon fish gelatine, and 
when injected into rabbits produced a fever similar to malaria. 
They named it the bacillus malaria. 

The malarial parasites were undoubtedly seen and described 




Fig. i. — Charles Louis Alphonse Laveran, the discoverer of the parasite of malaria. 



/ 



INTRODUCTION 21 

before Laveran discovered them. In 1847 Meckel, who first 
discovered malarial pigment, described bodies containing pig- 
ment which correspond to the malarial parasites. Virchow, 
in 1849, in a description of the pigment, depicted cells now 
known to be parasites, as did also Frerichs in 1866. The pig- 
ment was observed also by Dlauhy, Heschl, and Planer. None 
of these investigators, however, recognized the significance 
of these bodies, and their parasitic nature was not suspected 
until 1880 by Laveran, to whom all the more honor is due. 

Charles Louis Alphonse Laveran was born at Paris, June 
18, 1845. He entered the military service and was assigned 
to Algeria, where his brilliant discovery was made on Novem- 
ber 6, 1880, and announced to the Paris Academy of Medicine 
November 23, 1880. He was using a one-sixth inch dry lens 
when examining the blood. He says, 1 "My first researches 
date from 1878; at this time I was on duty in the hospital of 
Bone, in Algeria, and a great number of my patients were 
suffering with malarial fever. I had occasion to perform 
autopsies upon several subjects of pernicious malaria, and to 
study melanemia which had already been observed, but was 
not considered as a constant change in malaria, nor as a spe- 
cific lesion of that disease. I was struck by the singular appear- 
ance of granulations of black pigment, especially in the liver 
and in the cerebral vessels, and I endeavored to follow, in 
the blood of patients suffering with malarial fever, the study 
of the formation of pigment. I found in the blood leucocytes 
charged with pigment, already seen by other observers, but 
besides melaniferous leucocytes, spherical bodies, varying in 
size, pigmented, endowed with amoeboid motion, and pig- 
mented crescentic bodies attracted my attention. I supposed 
at that time that these were parasites. 

"In 1880, at the military hospital of Constantine, I discov- 
ered, besides the spherical pigmented bodies, in the blood of 
a malarial subject filiform elements resembling flagella, which 
writhed with great, vivacity and displaced the neighboring cor- 
puscles. From then I had no further doubt as to the parasitic 
nature of these elements which I had found in the blood." 

Laveran's discovery was not accepted by the medical world 



22 THE STUDY OF MALARIA 

until several years later; now it has been confirmed the world 
over. Among Americans who first corroborated Laveran's 
views may be mentioned Sternberg, Councilman and Abbott, 
Osier, James, Dock, Thayer and Hewetson, Barker, Woldert 
and Welch. 

The discoveries of Golgi in 1885 were of great importance 
with reference to the life history of the parasite. He was able 
to follow tertian and quartan parasites throughout the endogen- 
ous cycle of development, and showed that a close relationship 
existed between certain phases of parasitic growth and certain 
stages of the paroxysm. Other Italian investigators proved 
the same for the estivo-autumnal parasites. 

A vague suspicion that malaria and mosquitoes were in some 
indefinite way connected has been entertained in certain coun- 
tries for a long period. A definite mosquito theory, however, 
was born in America. While reference is sometimes made to 
a paper on the "Mosquital Origin of Malarial Disease," sup- 
posed to have been published by Dr. John Crawford in the 
Baltimore Observer, 1807, no such article has been found, 
and the reference is probably erroneous. 

In 1848 Dr. Josiah Nott, 2 of Mobile, published a paper upon 
yellow fever, in which he maintained the dissemination of that 
disease by insects, and suggested that malaria was spread by 
the "mosquito of the lowlands." 

The most complete theory was proposed by King 3 in 1883. 
His views are supported by nineteen arguments, most of which 
are incontestable at the present day. 

That mosquitoes are agents in the spread of malaria was 
advanced by Koch in 1884, by Laveran in 1884, by Fliigge in 
1 89 1, by Manson in 1894, and by Bignami in 1896. 

Undertaking the work at Manson's suggestion, and after 
several years (1895-1898) of toil and discouragement, Ross 
proved conclusively that certain species of mosquitoes are con- 
cerned in the dissemination of malaria. The debt owed him 
by mankind was acknowledged by the gift of a Nobel prize; 
his own feelings over the discovery are expressed in these lines, 
which he wrote : 




Fig. 2. — Major Ronald Ross, the discoverer of the role of the mosquito. 



INTRODUCTION 23 

"This day relenting God 

Hath placed within my hand 
A wondrous thing, and God 
Be praised. At his command 

"Seeking His secret deeds, 

With tears and toiling breath, 
I find thy cunning seeds, 
Oh million-murdering death. 

"I know this little thing 

A myriad men will save ; 
Oh, death, where is thy sting, 
Thy victory, oh grave?" 

A discovery, secondary in importance only to those of 
Laveran and of Ross, was made by MacCallum in 1898, who 
demonstrated that the flagella represent male sexual elements, 
analogous to spermatozoa. 

HISTORY OF HEMOGLOBINURIC FEVER 

It is probably unique in historical pathology that a complex 
of symptoms so striking as hemoglobinuric fever should have 
such an obscure history. As this obscurity is intimately asso- 
ciated with the etiology and symptomatology of the condition 
an investigation of some of the factors in its history is not 
without interest. After a short statement of the history of 
hemoglobinuric fever we will briefly consider how far it has 
been influenced by (1) its confusion with bilious remittent 
fever and yellow fever, (2) the introduction of cinchona bark 
and its alkaloids into the treatment of malaria, and (3) the 
advent of Europeans into endemic regions. . 

In the years from 1850 to 1853 blackwater fever was de- 
scribed by Lebeau, Daulle, and Leroy de Mericourt, physicians 
of the French navy, who observed it in Madagascar, and espe- 
cially on the Island of Nossi Be, off the northwest coast of 
the former island. They named the condition icteric pernicious 
fever. In 1861 cases observed in the Antilles, Guiana, and 
Senegal were described by Dutrouleau as hematuria bilious 
fever. In the early sixties Barthelemy-Benoit also described 
hematuric bilious fever, and in 1874 appeared the monograph 
of Berenger-Feraud on melanuric bilious fever. This writer 



24 THE STUDY OF MALARIA 

states that the disease has existed in Goree since 1845, an d in 
St. Louis, in Senegal, according to the hospital records of that 
city, at least since 1820, shortly after the settling of the Euro- 
peans there. The first twenty-three settlers at Gabun, in 1843, 
were attacked with blackwater fever and almost all of them 
died. A great increase in frequency has occurred since 1850. 

Crosse 4 believes his own case, in 1888, to be the first on 
record in the Niger Territories, though he states that the 
disease was said by old coasters to have existed in the Niger 
Delta since 1882. F. Plehn 5 does not believe the disease to 
be of recent introduction into West Africa, but attributes its 
comparatively late recognition to two facts — first, that the 
susceptible population, who formerly lived as traders on an- 
chored hulks, began to take up their abode on the shore; 
second, that the disease was formerly confounded with yellow 
fever. It has been known in Senegambia since 1855, 6 and in 
the Dutch East Indies since the Atjeh War, 1874-78. 7 Cal- 
mette saw a number of cases in Gabun in 1886-87, an d Fluit, 
in San Juan del Stir, has seen numerous cases since 1850. 8 
The condition was not described in India until 1855, and 
Sambon 9 regards this as conclusive of its recent introduction, 
as "it would be absurd to think that it could have escaped the 
attention of such men as Annesley, Chevers, Carter, Martin, 
Fayrer, Morehead, and Maclean had they met with it." 

Dr. Elliotson, 10 in 1832, mentioned a case of ague accom- 
panied by a discharge of bloody urine during the cold stage. 

Todd, 110 in 1849, asserted that "a state of general cachexia, 
such as often occurs in scurvy, may bring on hematuria, or 
such as results from an aguish state brought on by the malaria 
of marshy districts." 

In the United States hemoglobinuric fever was first de- 
scribed by Dr. J. C. Cummings, ia of Monroe, Louisiana, in 
1859. He reported 6 cases, and refers to numerous cases 
during the previous season. Faget 12 treated the disease as 
early as 1859, and states that cases with hematuria and 
hematemesis had frequently been seen in New Orleans and 
been mistaken for yellow fever. Inasmuch as Faget consid- 
ered hematemesis a common symptom of hemoglobinuric fever, 



INTRODUCTION 25 

it is possible that he himself confounded the two diseases in 
some instances. In 1867 Dr. T. C. Osborn, 13 of Greensboro, 
Ala., observed 10 cases, 5 of which ended fatally, some with 
anuria and uremia. All the patients had been repeatedly at- 
tacked with malaria. A few months later his son, Dr. J. D. 
Osborn, 14 read a paper before the Greensboro Medical Society, 
from which it is evident that the disease was becoming more 
prevalent, and that the country people were regarding it as 
yellow fever. Dr. H. C. Ghent, 15 of Port Sullivan, Texas, in 
1866 reported hemoglobinuric fever endemic in parts of Texas. 
In March, 1869, Dr. R. F. Michel, of Montgomery, Ala., read 
a paper before the Medical Association of the State of Alabama 
in which he spoke of the disease as "a malignant malarial 
fever, following repeated attacks of intermittent, characterized 
by intense nausea and vomiting, very rapid and complete jaun- 
diced condition of the surface as well as most of the internal 
organs of the body, an impacted gall-bladder, and hemorrhages 
from the kidneys. These phenomena presented themselves in 
an almost uninterrupted link, attended by remissions and exac- 
erbations. It is a fever peculiar to the United States." He 
recorded the morbid anatomy in one of his fatal cases. In 
Arkansas hemoglobinuric fever was first recorded by Dr. E. 
R. Duvall, of Fort Smith, in a paper read before the State 
Society in 1871. He believed the case he recorded to be the 
first to occur in the State. This paper is said to be a model 
of accurate clinic observation. In 1880 Dr. G. B. Malone, in 
Monroe County, Arkansas, reported 155 cases met in his prac- 
tice. The affection was first reported in Georgia by Dr. W. 
A. Greene, of Americus, in 1872, and in North Carolina by 
Dr. Norcom, of Edenton, in 1874. Norcom asserts that the 
disease did not, as some claimed, make its first appearance a 
few years ago, but that it had long been recognized. Dr. 
McDaniel, 10 of Camden, Alabama, described hemoglobinuric 
fever in 1874, and says, "In calling up my own reminiscences, 
I am sure that I have occasionally ever since my boyhood seen 
isolated cases of what was considered intense bilious fever with 
the surfaces and under tissues stained deeply yellow and with 
the urine deep red. They were nearly all fatal, and were 



26 THE STUDY OF MALARIA 

called in older phrase "bilious congestive," and in more recent 
"pernicious bilious." I have also, but more rarely, known 
groups of similar cases associated, say 3 or 4 cases occurring 
on the same premises or in the same family, about the same 
time. All such cases, in addition to the deep so-called bilious 
color and the red urine, had jactitation, suspirous breathing, 
inordinate thirst, and vomiting of various shaded and tinted 
so-called bilious matters. By diligently inquiring I have ascer- 
tained that very many old physicians, some of whom have 
now retired from practice, are satisfied that they have observed 
similar cases, sometimes singly and sometimes in groups. 

The late-lamented Dr. A. G. Mabry, in a report of a case 
of intermitting icterode hematuric fever made to this associa- 
tion in 1870, says, "It is a mistake to suppose that this is a 
new form of disease. More than twenty-five years ago I 
treated, in the vicinity of Selma, cases of intermitting fever 
presenting in a marked degree all the symptoms characteristic 
of these cases at the present day." 

The acrimonious dispute of the earliest writers on the sub- 
ject of what constituted the coloring matter of the urine is 
parallelled only by that occurring later concerning quinine in 
the treatment. While Daulle and Berenger-Feraud stoutly 
maintained that the dark color was due to the presence of bile 
in the urine, Dutrouleau, Pellarin, Barthelemy-Benoit, Anto- 
niades, and Corre ascribed it to blood. It is remarkable that 
none of the first American writers attributed the color of 
the urine to bile, but considered it due to blood. Corre ( 1881 ) 
and Karamitsas (1882) proved that the process was a hemo- 
globinuria instead of a hematuria. 

The credit of first directing attention to the etiologic rela- 
tion between quinine and hemoglobinuric fever is generally 
credited to Tomaselli, who published his first observations in 
1874, but this is an error. At a meeting of the Greek Medical 
Society, November 6, 1858, Veretas 15 reported that the major- 
ity of physicians practising in the marshy regions of Greece 
had noticed hematuria following the administration of quinine. 
He adds, "Among these observers my father has a place, hav- 
ing attentively observed this action of the medicament not 



INTRODUCTION 27 

only in several other persons, but in himself also, unfortunately, 
as he was for a long time tormented with intermittent fever 
during his long residence at Vonitsa." Konsola 15 is said to 
have observed similar cases in 1858. During this year, also, 
Antoniades published an article on "Hemorrhages and Par- 
ticularly Hematuria in Intermittent Fever," in which he op- 
poses the theory that quinine is a cause. Other Greek physi- 
cians whose observations were published before those of Toma- 
selli are Papavassilou, Rizopoulos, and Karamitsas. 

1. The close relationship between malaria and blackwater 
fever renders it easily understood why the latter might have 
been confounded with bilious remittent fever. Moreover, the 
early pyretologists almost completely ignored the condition of 
the urine in fevers. Hence, in a clinical scene, preceded by or 
opened with ordinary malarial paroxysms and characterized 
by dark urine, between the color of which and the bilious urine 
of bilious remittent fever there are all degrees, it is slight 
wonder that the two conditions were confounded. 

This probably occurred chiefly in India and to a less extent 
in certain portions of Africa and America. One is struck, on 
reading accounts of the Indian fevers, with the description of 
the intense jaundice of the skin and scleras, out of all propor- 
tion to this symptom in the bilious remittent fevers of the 
present day. In fact, some of these descriptions — for instance, 
Johnson's 16 of his first case in India — lack only the mention 
of the characteristic urine, about which the author is altogether 
silent, to make a fairly complete case of hemoglobinuric fever. 
Cleghorn 17 graphically depicts what he regards as a form of 
tertian fever, accompanied with hemorrhages, dark urine, deep 
jaundice, and other symptoms of hemoglobinuric fever. Since 
it is reasonably certain that there was no yellow fever in 
Minorca during the period of Cleghorn's sojourn in the island, 
namely from 1744 to 1749, it may reasonably be inferred that 
he saw cases of blackwater fever. 

The fact that the early history of hemoglobinuric fever opens 
with disputes as to whether the coloring matter of the urine 
was due to blood or to bile is evidence of the confusion by 
some observers between hemoglobinuric fever and bilious re- 



28 THE STUDY OF MALARIA 

mittent fever, since formerly bile and malaria were practically 
synonymous. 

It has been mentioned that the first reliable records of the 
existence of hemoglobinuric fever were, according to Berenger- 
Feraud, those of the hospital of St. Louis in Senegal, where 
it is shown to have existed as early as 1820. It is a singular 
coincidence that this city afforded, in 1778, the first epidemic 
of yellow fever occurring in Africa. 18 Later Plehn 5 gave as 
one of his reasons for believing that hemoglobinuric fever was 
not a new disease in West Africa, that it had formerly been 
mistaken for yellow fever. Besides Senegal, two of the other 
regions where hemoglobinuric fever was first seen, the West 
Indies and Guiana, were yellow-fever foci. In the United 
States we have the early statement of Dr. J. D. Osborne that 
the condition was then regarded as yellow fever. 

The similarity of the symptoms and the relative immunity 
of the black race to both diseases render the mistake somewhat 
excusable. As recently as 1897 Below 448 maintained the iden- 
tity of yellow fever and blackwater fever. 

2. Cinchona bark was introduced into Europe in 1640 by 
the Countess del Cinchon, wife of the vice-regent of Peru, in 
whose honor it has received its name. The efficacy of the bark 
in malaria was first known to the Indians in the region of 
Loxa, in the southern portion of Ecuador. The Corregidor 
of Loxa, hearing of the severe illness of the countess with 
tertian fever at Lima, in 1638, advised her physician, de Vega, 
to give the bark a trial, which effected a prompt cure, and in 
those days was regarded as nothing short of miraculous. 
When the countess returned to Spain she took a supply of the 
bark with her. Here it seems first to have been employed 
chiefly by the Jesuits, who introduced it into Rome in 1649. 
It was then known as countess' powder, or Jesuits' powder. 
Its use was antagonized by other religious denominations and 
by the medical profession. Bark was imported into England 
in 1 671 by Sir Robert Talbot, an English quack, who kept the 
remedy a secret and sold it for one hundred louis d'or per 
pound. Louis XIV, who was attacked with a rebellious and 
severe intermittent in the year 1679, was cured by Talbot with 



INTRODUCTION 29 

a concentrated vinous tincture of the bark, purchased and 
made public the secret remedy, for which he paid £48,000 and 
a life annuity of £2000. 

In India the remedy was employed by Bogue 20 as early as 
1657. In these times in Spanish- America, where the bark was 
indigenous, extraordinary methods were employed to prevent 
the nature of the drug becoming recognized. But during the 
eighteenth century cinchona bark was almost universally 
known. Lind is said to have employed in Lower Senegal, 
during 1765, over 140 pounds of the bark. In 17 14 Ramaz- 
zini 21 wrote that should a fever patient die it was considered a 
crime not to have employed cinchona. In fact, so widespread 
was the use of large doses of bark that Calmenero (1647), 
Casati (1661), Daval (1684), Ramazzini (1714), and others 
wrote vehemently against the abuse of the drug. 

Pelletier and Caventou, in 1820, succeeded in isolating 
quinine from the bark. 

The institution of cinchona plantations in Java in 1854 and 
in Ceylon in 1859 caused a drop in the price of quinine, which 
had formerly sold for its actual weight in gold, to one-twenti- 
eth the original price. 

Marchiafava and Bignami 22 seek to explain the seeming late 
appearance of hemoglobinuric fever by the use of quinine 
becoming prevalent at the time when the disease was first 
described. It is probable that this factor has caused an increase 
in certain localities, but a comparison of the history of the 
disease with that of the drug shows no very intimate chrono- 
logic relations. Further, blackwater fever is on the decrease 
in some regions where the use of quinine is becoming more 
general. This is reported to be the case in German East Africa 
by Meixner, 23 in Cameroon by Ziemann, 23 in Togo by A. 
Plehn, 24 and by Kohlbrugge 7 in the Malay Archipelago. The 
large number of cases occurring without the previous use of 
quinine should also be considered. 

3. A consideration of the importance, in the history of 
hemoglobinuric fever, of the immigration of Europeans into 
regions where the condition is endemic involves the history 
of the tropics and subtropics. . This factor is manifestly an 



30 THE STUDY OF MALARIA 

essential in countries where the natives are nearly immune, as 
in parts of Africa. Historic events, which were probably 
potent in the development of blackwater fever, were the dis- 
covery of America, the Portuguese discoveries and settlements 
on the coast of Africa, the African slave trade and the later 
efforts to abolish the same, the advent to Africa of mission- 
aries and explorers, especially in the early part of the nine- 
teenth century, and the operations of the East India Company. 
The accession of Europeans was influential in the history 
of hemoglobinuric fever in several ways — by the increase of 
susceptible population, by the importation of quinine, and by 
the advent of physicians competent to recognize and to describe 
the disease. 



CHAPTER II 

GEOGRAPHIC DISTRIBUTION 

North America. — In the United States it is chiefly the 
southeastern portion in which malaria is most prevalent. Along 
the Atlantic coast, south of New York and especially the low- 
lands of Maryland and of Virginia, and in the Carolinas, 
Georgia, and Florida the disease occurs frequently. Along the 
Gulf coast and up the Mississippi River and its tributaries 
malaria is widely prevalent. The portions of the States lying 
along the Appalachian Range are almost exempt, but the dis- 
ease appears as the Mississippi River and the Atlantic coast 
upon either side are approached. West of the Mississippi, 
Arkansas, Louisiana, and Texas present the most numerous 
foci of malaria. In portions of Pennsylvania and New York 
autochthonous cases are not infrequently observed. In the 
more" southern New England States malaria is still encountered, 
and in some places is even increasing in frequency. In the 
neighborhood of the Great Lakes malaria is very rare, except- 
ing, possibly, that of Lake Erie and of Lake Michigan. In 
the Central States malaria has almost or quite disappeared, 
except in certain low river valleys. Along the Pacific coast 
the disease is not so frequent as along the Atlantic. In Wash- 
ington it occurs in the Puget Sound Basin and the Columbia 
River, Chehalis, and the Yakima valleys. In Oregon malaria 
is found in the Columbia, Williamette, Rogue, and the Uma- 
tilla valleys, and in California in the Sacramento, San Joaquin, 
Tulare, Kern, and Santa Clara valleys. In certain parts of 
New Mexico malaria is occasionally met with. 

Canada is free from paludism except along the northern 
shore of Lake Ontario. 

In Mexico severe forms of malaria occur, particularly in 
the low coast regions. 

31 



32 THE STUDY OF MALARIA 

Malaria abounds in Central America along the Atlantic coast 
and to a less extent upon the Pacific side. 

South America. — The eastern coast of South America is 
more intensely infested with malaria than is the western coast. 
Venezuela (in the valleys), Guiana, and the greater portion of 
Brazil are highly malarial. Portions of Paraguay and of 
Bolivia afford a great many cases, while the disease is much 
less prevalent in Uruguay and almost absent from the Argen- 
tine Republic. On the Pacific border the deep valleys of Peru 
and of Ecuador are malarial centers. 

The entire island of Cuba is malarial to a greater or less 
extent, as is also Jamaica. Of the Lesser Antilles, St. Vin- 
cent, Antigua, and Barbadoes are relatively exempt. Malaria 
is said to be almost unknown in the Bermudas. 

Europe. — Great Britain, once infested, is now free from 
endemic malaria. In Germany the disease occurs infrequently 
in the Rhine and Danube valleys and near the mouths of rivers 
along the coast. Malaria is met in Holland, chiefly upon the 
island of Zeeland and in North and South Holland. The 
valley of the Danube, in Austria, affords a considerable num- 
ber of cases. There are few regions in Hungary in which the 
disease does not occur, but it is especially along the western 
half of the southern border that it is prevalent. The marshes 
along the west coast and in the south of France give rise to 
a number of cases of malaria. In Spain and Portugal malaria 
occurs in the coast regions and in the larger river valleys. The 
disease is practically unknown in Norway, but is occasionally 
reported from Sweden, as well as from certain of the islands 
of Denmark. In Russia it is in the southern portion, particu- 
larly along the coasts and along the valleys of the rivers flow- 
ing southward, that malaria is encountered. Cases are occa- 
sionally observed in the southwest of Switzerland. The por- 
tions of Bulgaria most highly malarial are the Danube valley, 
the coast region, and the southern part. Almost the whole of 
Italy is sorely afflicted with malaria, as are also Sicily and 
Sardinia. Greece is the most severely scourged country of 
Europe. It is said that in the plains of Thessaly, Phthiotis, 



GEOGRAPHIC DISTRIBUTION 33 

Acarnania, Boeotia, Elis, Messenia, Argos, and Laconia hardly 
a single inhabitant escapes the disease. 

Asia.- — Asia Minor, Arabia, and Persia present foci of mala- 
ria, both in the coast neighborhoods and in the interior low- 
lands. In the swampy regions of Afghanistan and Beloochis- 
tan malaria is'common and severe. In India portions of the 
northwest provinces and of the Bengal and Bombay Presiden- 
cies are intensely malarial. The foothills of the Himalayas, 
the Duars, and Terai are famous malarial seats. Both the 
coast regions and the interior highlands of Ceylon are endemic 
territory. Burmah, Siam, the Malay Peninsula, and French 
Indo-China are malarial in portions of their extent, and parts 
of China are intensely infested. Malaria is found in Japan, 
Formosa, and the Philippines, and portions of the East Indies 
are among the most highly malarial regions of the world. 

Africa. — On the west coast the territory, between the 
Senegal and the Congo Rivers, is headquarters for malaria of 
malignant type. Approaching South Africa the disease dimin- 
ishes in frequency and in severity. On the east the region 
from Delagoa Bay to Eritrea is malarial. In the interior of 
Central Africa, excepting the high elevations, malaria is wide- 
spread. Malaria abounds in Madagascar excepting upon the 
northeast coast and the mountainous interior. Reunion and 
Mauritius are also malarial. In Egypt it is chiefly the region 
overflowed by the Nile in which the disease is most prevalent. 
Malaria abounds about the coasts and marshes of Algeria. 

In Australia malaria occurs from Cape York to Brisbane, 
on the east coast, diminishing toward the south. New Zealand 
is apparently free from malaria, and the Sandwich Islands and 
most of the other Pacific islands are remarkably exempt. 

The relative frequency of the forms of malarial infection 
varies greatly. It may be stated as a general proposition that 
the quartan is the rarest form, the tertian is the form prevail- 
ing in temperate regions, and the estivo-autumnal in warm and 
* hot climates. There are regions, however, in which the quartan 
predominates, as in certain portions of Italy and of India; 
in other localities it is the only form of malaria present, as 
upon the island Merite, of the Bismarck Archipelago. 
3 



34 THE STUDY OF MALARIA 

The following table shows the relative frequency of the 
types of malaria in various regions : 



Locality. Authority. 

Texas Moore" 

Georgia Curry 20 

Camp Wikoff Ewing"' , 

New Orleans Charity Hospital Records 2 

Baltimore Thayer and Hewetson 29 . . , 

Panama .Kendall 30 

St. Lucia Gray and Low 31 , 

Panama Gorgas 32 

Italy Koch 33 , 

Italy Koch 34 

Greece Cardamatis and Diamessis 3 

Bulgaria Mollow 30 

Italy Italian Statistics 37 

British Malaya Wright 38 

British Malaya Watson 38 , 

Philippines Craig 39 

India Hope 40 

Cyprus Williamson 41 

East Indies Koch 42 

Philippines Chamberlain 43 , 

India Rogers 44 

India Buchanan 45 

Assam Bentley 40 

Japan Tsuzuki 47 

Togo Ziemann 48 

German East Africa. . . Meixner 49 

German East Africa. . . Grothusen 40 

Senegal Thiroux and d'Anfreville 5 

German East Africa. . . Kudicke 51 

German East Africa . . . Exner 52 

German East Africa . . . Ollwig 52 

German East Africa. . . Schornich 62 



Tertic 


in. Quar- 


Estivo-au- 




tan. 


tumnal. 


23 





30 


34 





16 


74 





26l 


373 


I 


203 


33* 


5 


188 


22 





291 


12 


2 


109 


4,812 


8 


10,81 s 


32 


5 


78 


202 


15 


191 


«7 


3 


145 


99 


10 


67 


2,392 


6,846 


23,520 


78 


56 


117 


19 


4 


28 


98 


8 


272 


217 


933 


547 


12 


8 


4 


57 


119 


123 


55 


3 


62 


L372 


7i 


1,3" 


56 


12 


118 


134 


46 


74 


345 


12 


107 


1 


7 


32 


5 


1 


102 


5 


7 


68 


7 


44 


266 


3 


2 


118 


11 


4 


328 


7 





134 


1 


2 


130 



Infections with more than one form of the parasite are not 
uncommon. Of these a combination of the tertian and the 
estivo-autumnal is the most frequent, the tertian with the quar- 
tan being rare, and the three forms together very rare. 

GEOGRAPHIC DISTRIBUTION OF HEMOGLOBINURIC FEVER 

In North America hemoglobinuric fever is found in the 
Southern States, especially parts of Texas, Louisiana, Arkan- 
sas, Mississippi, Tennessee, Alabama, Georgia, Florida, North 
Carolina, South Carolina, and Virginia. It is prevalent in 
Central America, particularly in Honduras, Nicaragua, and 
Costa Rica. It is found in the Greater Antilles, but appears 
to be rare in Hayti. In the Lesser Antilles it is more common 



GEOGRAPHIC DISTRIBUTION 35 

on the islands of Guadeloupe and Martinique. Numerous cases 
have been reported from Panama. 

In South America hemoglobinuric fever prevails more nota- 
bly on the north and east coasts, in Venezuela, Guiana, and 
Brazil, at least as far south as Rio de Janeiro. 

It is rare in Italy, but rather more common in Sicily, Sar- 
dinia, and Greece. Otto 53 has reported an autochthonous case 
from Krakau. It has appeared in some of the valleys of Spain, 
and, according to Schoo, was formerly observed in Holland. 

The regions in India in which hemoglobinuric fever is en- 
demic are as follows : Between the Ganges River and the 
Himalayas in Behar Province; between the Godavari and the 
Mahandi Rivers in the Madras Presidency; a region in the 
Punjab between Meerut and the Indus River ; a region of which 
Nagpur is the center; certain localities in the region of Bom- 
bay ; and in Assam and in upper Burmah. It is found in Asia 
Minor, Cyprus, and Syria (being common in Palestine), the 
Malay Peninsula, Siam, Cochin-China, Tonking, and other 
portions of French Indo-China, and in Southern China. In 
the East Indies it appears in Sumatra, Java, Celebes, and more 
commonly in New Guinea and the Bismarck Archipelago. It 
has been reported from Formosa, but is comparatively rare in 
the Philippines. 

Tropical Africa is the home of blackwater fever. Here, 
between the parallels of 15° N. and 15° S., it has been one 
of the deadliest foes to civilization. On the West Coast it 
occurs from Senegal to Damara Land, especially in Sierra 
Leone, Gold Coast, Nigeria, Cameroon, and the Congo region. 
On the east it prevails from Somali Land to Delagoa Bay, par- 
ticularly in British and German East Africa and the Congo 
Free State, and is met with in the Bahr-el-Ghazal region and in 
Sudan. In Algeria, Laveran, 11 during a residence of five 
years, did not observe a single case and Brault 54 saw only one. 
However, Coste 52 has recently published his observations of 
25 cases treated during 1904-05 in the region of Arzew. It 
rages in parts of Madagascar and Reunion, and is known in 
Mauritius and the Comora Islands, notably Mayotte. The 
mountainous islands of the Gulf of Guinea afford a few cases. 



36 THE STUDY OF MALAEIA 

Thus it is seen that, while the peculiar geographic distribu- 
tion of hemoglobinuria is embraced by that of malaria, it is 
not coextensive with the latter. And here the relation ceases. 
While all localities in which blackwater fever exists endemi- 
cally are highly malarial, there are very extensive regions in 
which the severest forms of tropical malaria are rampant 
where hemoglobinuric fever is unknown. 

It has been attempted to explain the distribution by saying 
that the frequency of hemoglobinuria in a given locality is in 
direct ratio to the endemic index of that locality — that is, the 
percentage of native-born children whose blood harbors mala- 
rial parasites — but this explanation also presents difficulties, 
as the disease is not present in all localities whose endemic 
index is high. 

Wellman 58 maintains a close relationship between the geo- 
graphical distribution of Myzomyia funesta in Angola and 
that of blackwater fever. Daniels 57 believes that if the disease 
is due to one or all of several varieties of mosquitoes which he 
mentions, M. funestus must be one of those implicated. F. 
Plehn 58 suggested a possible relation between the geographic 
range of hemoglobinuric fever and that of certain mosquitoes. 

In certain localities the disease seems to be on the increase. 
Crosse 4 says that it is increasing in certain parts of West 
Africa. Manson 59 refers to the belief of competent observers 
that it is yearly becoming more common in Africa. Johnson 80 
and F. Plehn 61 assert that it is undoubtedly becoming more 
prevalent on the west coast of Africa, and A. Plehn 62 believes 
that it is increasing in frequency in New Guinea. The inhabi- 
tants of the region of Jalpaiguri, in India, are recently said 
to be alarmed at its increase in that section. 63 

On the other hand, there are places in which it is becoming 
less frequent. The medical report from German East Africa 
for the year 1903-04 shows a decrease from the preceding 
year. The report from Duala shows a steady annual decrease 
from 1 90 1 to 1904 inclusive. 49 Kohlbrngge 7 declares that it 
is becoming rarer in the Malay Archipelago. A. Plehn, 24 after 
mentioning the decrease in certain sections of West Africa, 
prophesied that in half a century this scourge of tropical Africa 



GEOGRAPHIC DISTRIBUTION 37 

would become, if not a historic reminiscence, at least an insig- 
nificant rarity. It is probably becoming less frequent in some 
of the Southern States. 

Epidemics of hemoglobinuric fever have been described. 
Masterman 64 states that in 1893 there was a regular epidemic 
of malaria in and around Jaffa, and among the fatal cases 
were a great many of hemoglobinuria. Says Plehn, 61 "Not 
infrequently the disease appears in epidemic form, as was 
the case several years ago in Goree, Quittah, and Bonny." 
Sambon 9 mentions several epidemics, as follows : "The disease 
broke out among the laborers employed in making the canal 
through the Isthmus of Corinth ; it attacked the Chinese labor- 
ers on the Congo Railway; and in 1885, according to Dr. 
Wenyon, of Fatshan, China, it ravaged, like a plague, the 
Chinese army on the Tonquin border of Kwangsi. In collec- 
tive dwellings — such as barracks, hospitals, schools — it may 
attack several persons at the same time. In 1885 it broke out 
in a prison in Castiades, Sardinia, attacking 24 out of 800 
convicts." 



CHAPTER III 

ETIOLOGY 

Depending as it does for its existence upon the life histories 
of three species of animals, malaria is of rather complex 
etiology. While within the blood of man the parasite is not 
subject to great variations of environment, no matter what the 
season or the latitude, nevertheless exposure to cold, wet 
or heat, dietary or other excesses, will have the effect of awak- 
ening latent malaria. 

But it is the influence of external factors upon the life his- 
tory of the mosquito that determines the greatest variations in 
the prevalence of malaria according to climate, season, tem- 
perature, rainfall, altitude, etc. 

Climate. — It may be said, as a general rule, that the fre- 
quency and virulence of malaria increase as we approach the 
equator. The conditions of warmth and moisture are more 
propitious for the development of parasites within the bodies 
of mosquitoes in tropic than in colder climates; this is espe- 
cially true of the estivo-autumnal form of the malarial parasite. 
Exposure to the heat of the tropical sun predisposes to the 
cerebral forms of pernicious malaria, and undue exposure to 
the sun's rays is ofttimes sufficient to stimulate sporulation 
of the parasites of latent malaria. 

With respect to latitude Hirsch 18 reached the following con- 
clusions as to the northern boundary of malaria in the northern 
hemisphere. The line starts from 55° N. on the western side 
of North America, sinks to 45° on its eastern side, rises to 
63° or 64° on the western side of the old world (Sweden and 
Finland), and runs across Northern Asia in about the latitude 

fa 
55 • 

Long before the discovery of the role of the mosquito in 
malaria it was known that the disease was not endemic unless 
the summer temperature maintained a certain average. Dur- 
ing the middle of the last century Drake 65 assumed that an 

38 



ETIOLOGY 39 

average summer temperature of sixty degrees is necessary to 
the existence of malaria, and that it will not prevail as an 
epidemic where the average temperature falls below sixty-five; 
also that the fever will occur in winter at all places where that 
season has a mean temperature of sixty degrees or upward. 
Hirsch maintained that the summer isobar of 59°-6o.8° F. 
marks the limit of the occurrence of malarial fever, and that 
those regions where the mean summer temperature does not 
reach that height are exempt from the disease. Curiously 
enough, it has been recently repeatedly demonstrated that this 
is the lowest temperature at which the parasite will develop 
in the body of the mosquito. 

Season. — While relapses may occur at any season, and in 
certain tropic regions fresh infections may occur during any 
period of the year, in all temperate and most tropic regions 
there are seasons during which the disease is especially preva- 
lent. This is commonly known as the malarial season, and 
varies according to latitude, temperature, rainfall, soil, etc. 

The season of primary attacks depends entirely upon the 
life history of the malaria-bearing mosquitoes. This season 
usually begins a few weeks after the first brood of anophelines 
appears, which is at the height of summer, and continues, in 
temperate climates, until after the nights become cool. In 
each individual locality the beginning of the season is rather 
definite, the disease recurring at a certain period each year 
with more or less exactitude. In most of the regions of the 
Southern States the malarial season begins in the earlier half 
of July. In the latitude of Baltimore the most notable increase 
in cases begins during August. The malarial season in Cali- 
fornia is from August to October. 

The following seasonal distribution of malaria in Panama 
is compiled from the "Reports of the Department of Sanita- 
tion of the Isthmian Canal Commission," and is the aggregate 
of the three years, 1906- 1908: 

January 4,301 July 6,399 

February 3,624 August 6,319 

March 3,591 September 5,384 

April 2,400 October 5.276 

May 2,127 November 3,814 

June 3,900 December 3,647 



40 



THE STUDY OF MALARIA 



In Italy a large number of cases from various sources 3 
are distributed as follows : 



January 8,567 

February 6,811 

March 8,124 

April 9,302 

May 11,101 

June 15,106 



July 41,855 

August 61,335 

September 52,525 

October 35,640 

November 23,298 

December 12,670 



In Guiana the season of greatest prevalence is said to be 
from October to December inclusive; in St. Lucia, W. I., from 
January to March; in Germany, from the end of July to the 
middle of September; Holland, from the middle of May to 
middle of September; France, from July to November; Bul- 
garia, May to October ; Italy, from the end of June to Novem- 
ber; Greece, from May to November; in Tonkin, from April 
to November; Calcutta, from October to December; Cyprus^ 





---ffp- 


' 




— 1-~ 




iffliilffl 


L-pj-i-i — H-- 1 — l"--f -1 


J irrf x -n+Hrr 


tiffft 


1 Illl'iH 






jb\m 










f TH-'lTn" 


^^nMi^ii+l 


=:||e|||| 


ittti 


-UUlfo 


a 
















EE::i::::::;: 


-:|""|::~i"-3 










±+ 
















































































































































!|| J 




































BBB 






::ir:|| :: E: :: :: : ; 


"S : *'""TOT 


f u 1 1 1 1 








H" 














































ii :: 




liff^ife 


:|| 


±y±g£ 










: 






¥. 


; 


j. 








I'll 




iith TnTiTT 1 1 1 1 ' 1 1 


= 44i4+W-Ut+r 


.1! l! 1,1 ! 




| 


T 







Fig. 3. — Diagram showing relation between rainfall and malaria (Plehn). 

Malaria morbidity. 

. — . — . — . — . Rainfall. 
Rainy days. 

from July to October; Singapore, April to July; German 
New Guinea, from November to June ; Northern Africa, from 
the middle of June to November ; and in German East Africa, 
from April to July. 

Where both tertian and estivo-autumnal malaria are endemic 
the malarial season is usually ushered in by cases of the for- 
mer, the estivo-autumnal variety appearing at the height of 



ETIOLOGY 



41 



the season. The pernicious forms of malaria occur with great- 
est frequence at the height of estivo-autumnal prevalence. In 
Italy quartan malaria begins late in the summer and continues 
late in the fall. In America this variety is too infrequent to 
justify any definite conclusions. Mixed and multiple infec- 
tions occur more frequently late in the season than early. 

Rainfall. — The influence of rainfall upon the extent of 
malaria is very decided. Breeding places for mosquitoes are 



S >, u 



n u — 













X- 


uA. 




1 




10 


H 


'0 


A 


FT 














TO 


\ 




1* 




7 


'2 


S, 


iO 
















i 


\ \ 




3 




? 


7 


X 


, j 


E4--.-, 














/ 


y< 




f 




7 


1 


i« 


F 


f 


.^ 














L 




f 




t> 


8 


zl^ 




I' > 












<L 


/■S 


/ 




t 




s 


! 


"—IL .* 


/--- 


-#- -j 


_t 










X. 


r^ 




_t 


7 




<i 


r 


L V 


--JI 




-H, 












/A 


L— -£-- 


fc 


? 




1 


H 


4*. ■»**« ,u/< *u ( 


s/ f \ 


A 














1 \ 


/ 




3 




1- 


% 


8 


\ 


1 














A 1 


> r 




10 




1 


1 


I z 


J 


\ j 












- ^ 


1 


\/ ' 


L~ 


a 








<J~, M£ "* 


L 







Fig. 4. — Relation between rainfall, ground water, and malaria (Ziemann). 



essential in the etiology of malaria, and limited pools, such as 
result from a fall of rain, are well suited to the taste of the 
malarial mosquitoes. 

Rain has a twofold effect upon the prevalence of malaria. 
First, exposure to wet is not infrequently followed by a recru- 
descence of a former infection. This effect is usually imme- 
diate. Second, rainfall produces breeding pools for the dis- 



42 THE STUDY OF MALARIA 

seminators of malaria. The effect of fresh breeding places 
is not shown immediately. Allowing twenty days for the 
aquatic stages of the mosquito, ten days for the mosquito cycle 
of the parasite, and a like period for the incubative stage in 
man, it would be, obviously, several weeks before an increase 
in malaria could be expected from such a source. This is 
well exemplified in the tropics, where so much depends upon 
rainfall. Here the height of the malaria curve is attained 
toward the end of the rainy season or shortly after. 

A heavy rainfall in the spring and early summer has long- 
had the reputation of being favorable to the spread of malaria. 

While rainfall is essential to the development of malaria, 
if excessive it may have the opposite effect by scouring breed- 
ing pools and destroying the contained ova and young of the 
mosquito. Moderate rains at short intervals are more produc- 
tive of breeding pools than heavy downpours at long intervals. 
Hence, the number of rainy days, as well as the actual rainfall 
in inches, is a factor in the etiology of malaria. 

In very low countries rainy years may be healthy years. 
This is said to be the case in the Netherlands. 66 

Dew and a high atmospheric moisture were formerly accred- 
ited with being factors in the cause of malaria. This was 
doubtless on account of the well-recognized danger of con- 
tracting malaria between sunset and sunrise. Other than as 
an index of ground-moisture it is doubtful whether atmos- 
pheric moisture bears any relation to primary infections with 
malaria. 

Soil. — The chemical composition of the soil has an effect 
upon the reign of malaria only so far as the relation of the 
soil to the retention of water is concerned. More depends 
upon the physical conformation than upon the geologic char- 
acteristics of the soil. As a rule, clay soils retain moisture 
better than the sandy, though there are exceptions. Rocky 
regions are less apt to harbor breeding pools because of good 
drainage, but pools upon a rock-bed are very persistent. The 
soil must be of such a character as to retain surface water 
sufficiently long for the aquatic stages of mosquito life to be 
completed. 



ETIOLOGY 43 

More depends upon the nature of the subsoil than that of 
the surface soil. Even where the surface soil is very porous, 
an impervious subsoil favors the accumulation of surface water 
by preventing further percolation. Thus the height of the 
ground water during the malarial season bears a close relation 
to the volume of the malarial endemic. Proximity to col- 
lections of water, by raising the height of the ground water, 
favors the development of malaria. 

Topography. — In countries designated malarial, regions en- 
tirely free from the disease are not uncommon. In a region 
within a short distance of a severely scourged locality malaria 
may be entirely absent. The difference in the prevalence of 
malaria within limited areas is dependent, in great measure, 
upon the physical characteristics of the surface of the land. 

It has been known for centuries that malaria is partial to 
low marshy places, swamps, lakesides, low coast levels, and 
river valleys, and especially the deltas of large rivers. The 
cleaner the banks and the swifter the current of the streams 
at all stages the less apt they are to be malarious. Streams 
with sluggish or no currents, and with weedy banks which 
foster eddies, are breeding places for mosquitoes. 

Nearly two hundred years ago Lancisi 67 described noxious 
and harmless swamps. His description of the former depicts 
well the favorite breeding places of the malaria-bearing mos- 
quitoes. 

Drake 65 well describes the topography of the malarial region 
of the United States as follows: 

"In the maritime parts of Florida, Alabama, Mississippi, 
Louisiana, and Texas surface water is abundant, for one side 
of each rests on the Gulf, which has many inlets and little 
bays, the banks of which are inhabited. The rivers, more- 
over, are numerous, and as they approach the Gulf expand 
into broad estuaries or deltas. The delta of the Mississippi 
abounds in lakes, lagoons, and bayous. As we ascend this 
and the smaller rivers wide cypress and liquid-amber swamps, 
annually replenished, skirt both sides. The intervening plains 
are cut up by smaller streams, which have wide alluvions, 
often subjected to inundations, and the country between them 



44 THE STUDY OF MALARIA 

abounds in swamps, from which even the sandy pine-plateaus 
are not entirely free. This continues to be their condition 
till we reach the flanks of the Cumberland Mountains on the 
east and those of the Ozark Hills to the west. As we ascend 
the Mississippi to the mouth of the Missouri we find its annual 
floods leaving small lakes, ponds, swamps, and lagoons, which 
in the aggregate are of great extent and but partially drained 
or dried up before the next inundation. Now, as we have 
seen, the whole of this region is infested with autumnal fever 
beyond any other portion of the valley. 

"In North Alabama, Tennessee, and Kentucky swamps are 
almost unknown, except along the few rivers which have wide 
bottom lands, most of which, moreover, are exempt from 
inundation. The rivers, however, are sinuous, and in summer 
sluggish and pondy, and it is in their vicinity chiefly that 
autumnal fever prevails. In the States of Illinois, Indiana, 
and Ohio the rivers generally flow through wide valleys, many 
of which are liable to be overflowed. Small lakes, ponds, and 
swamps are also frequent in certain portions of these States, 
and it is precisely these localities which are most infested. To 
the east of all the States mentioned, as we climb the moun- 
tains, the surface water is no longer found in basins, and the 
streams generally have a rapid current, down narrow and 
rocky channels, and here autumnal fever nearly disappears, 
or when present is confined to the valley of some stagnating 
stream. Everywhere west of the States of Arkansas, Missouri, 
and Iowa surface water is scarce, the declivity of the plain 
which stretches from the Rocky Mountains favoring its escape, 
while the subjacent sand almost absorbs even considerable 
rivers. Thus, as we advance into that desert, we come at 
the same time to the limits of the surface water and of aut- 
umnal fever. In the North there is no deficiency, for the 
whole country is essentially lacustrine, and up to a certain 
latitude the fever prevails. Thus the shores of Lake Ontario 
and Lake Erie, with those of the southern extremity of Huron 
and Michigan, are infested, and suffer far more than the dry 
lands which surround them. But beyond these limits, on the 
shores of the two latter lakes and on those of Lake Superior, 



ETIOLOGY 45 

the fever, as we have seen, is never epidemic, although water 
is abundant; and still further North, where small lakes and 
their connecting streams exist in countless numbers, the disease 
is unknown, showing that, while water is essential to the pro- 
duction of this fever, other causes must cooperate to give it 
power." 

Canals, dams, stock, and other ponds, railroad and levee 
borrow pits and other collections of water, particularly when 
stagnant, often breed anopheline larvae, hence favoring the 
development of paludism. 

It is generally believed that salt marshes are never malari- 
ous, and that anopheles larvae cannot develop in sea-water. 
This is, however, not strictly true. DeVogel 68 has recently 
shown that anopheles larvse may develop in sea-water evapo- 
rated to half its initial volume, and a number of other observ- 
ers have found larvae in salt water. But marshes of pure 
sea-water are not nearly so noxious as those of brackish water, 
a mixture of salt and fresh water, which are famous anopheles 
breeders. It appears that in some instances where salt water 
is inimical to the development of the aquatic stages of mos- 
quitoes they may gradually become accustomed to the environ- 
ment. 

Altitude. — Malaria is essentially a disease of the low lands, 
high altitude being relatively exempt. This is partially ac- 
counted for by the better drainage of elevated altitudes and 
fewer pools in which malarial mosquitoes may breed. The 
lower temperature of high altitudes is also a factor in main- 
taining a low malarial morbidity in these regions. 

It is known that anopheline mosquitoes do not fly to great 
heights. Hence sleeping in an upper story or in a building 
situated high above the ground gives a measure of protection 
from malaria. Laborers employed in highly malarial sections, 
and who sleep in the surrounding hills, even of moderate alti- 
tude, often remain entirely free from infection. 

A few hundred feet in altitude may show a more marked 
difference in the prevalence of malaria than as many miles 
in latitude. 

The general rule that malaria is a disease of low countries 



46 THE STUDY OF MALARIA 

has some exceptions. This is especially true in the tropics, 
where the disease may be encountered at very high altitudes. 
It may be said that the altitude at which malaria may occur 
varies in inverse ratio to latitude. 

Malaria has been found on Lake Nyssa at an altitude of 
1,560 metres; at Colico, 2,500 metres; in the Himalaya Moun- 
tains, at 2,000 metres; in the Andes, at 2,500 metres; at Blan- 
tyre, at 3,000 feet; German East Africa, at 1,550 metres; at 
points in Central Africa, at heights of over 5,000 feet; and 
in some of the high-lying valleys of Syria, at altitudes of 
1,200 metres. 

Some of the cases in high altitudes reported as malaria may 
be mistakes in diagnosis; other cases may be malaria con- 
tracted in the lowlands. Thus Tosari, at an elevation of 1,777 
metres, had been cited as a place where malaria prevailed with- 
out the presence of mosquitoes, and this was used as an argu- 
ment against the "mosquito theory." Koch, 69 investigating 
the place in 1899, examined the blood of eighty-two children; 
in none was the parasite of malaria detected. The only case 
of malaria found was in a man who, twelve days before the 
beginning of his illness, had spent the night in a highly mala- 
rial place upon the coast. 

However, malaria is endemic in certain places of high alti- 
tude. Such are Eritrea, in altitudes of 1,750 metres; Upper 
Tonkin, at 1,000 metres; parts of Madagascar, at 1,100 metres; 
parts of Reunion Island, 1,200 metres; in Java, at 1,000 
metres; and in the Philippines it is said that, while certain 
valleys are almost free from malaria, the hills in the vicinity 
are notoriously infected. 70 Wright, 38 in British Malaya, found 
anopheles larvae in pools at an elevation of 2,300 feet. 

Earthquakes and volcanic eruptions have been followed by 
a great development of malaria. Examples are cited of Rome 
in 1703, in Reggio in 1783, and Palermo in 1828. Remark- 
able instances have occurred in Peru also. The most recent 
illustration is that of Amboina, in the East Indies, which had 
until 1835 been remarkably free from malaria. In that year 
a severe earthquake occurred, and since then the malaria has 
increased both in extent and intensity. 18 



ETIOLOGY 47 

Such results can be explained only by an increase of stagnant 
water following these violent disturbances, probably through 
the interruption of the flow of ground-water. 

Inundations. — Since very early times overflows have been 
recognized as a prolific cause of epidemics of malaria. Tacitus, 
Suetonious, Livy, Dionysius, Cassio, and Strabo mention such 
results from inundations of the Tiber. This stream experi- 
enced an overflow in 1695, which was described by Lancisi. 
The water covered a broad area of country, filling ditches, 
sewers, and canals. The following June, July, and August 
were extremely hot. An epidemic of malignant malarial fever 
ensued and, spreading far and wide, occasioned a great mor- 
tality. 

In giving a description of a trip up the Tigris River, Lind 71 
gives the following account of a curious strategem: "Here 
we were informed that the Arabs had broken down the banks 
of the river near Bassora, with a design to cover with water 
the deserts in its neighborhood. This, it seems, is the usual 
method of revenge taken by the Arabs for any injury done 
them by the Turks in Bassora, and it was represented to us 
as an act of the most shocking barbarity, since a general con- 
suming sickness would undoubtedly be the consequence. This 
was the case fifteen years before, when the Arabs, by demol- 
ishing the banks of this river, laid the environs of Bassora 
under water. The stagnating and putrid water in the adjacent 
country and the great quantity of dead and corrupted fish at 
that time lying upon the shore polluted the whole atmosphere 
and produced a putrid and mortal fever. Of this fever be- 
tween 12,000 and 14,000 of the inhabitants died; at the same 
time not above two or three of the Europeans who were set- 
tled there escaped with life." 

Epidemics of malaria following overflows of the Nile, 
Ganges, Indus, Euphrates, Niger, Senegal, Volga, Danube, 
Saone, Rhone, Loire, Mississippi, and other rivers have been 
described. 

The immediate effect of an inundation is to check the devel- 
opment of malaria. This is a result of a destructive effect of 
the flood upon the breeding pools of mosquitoes. It is only 



48 THE STUDY OF MALARIA 

after the waters have subsided and pools and marshes are 
left that the epidemic develops. 

Trees and Vegetation. — It was formerly believed that, 
while decaying vegetation was the cause of malaria, living 
plant life greatly retarded its development. Whole volumes 
have been devoted to this subject. It was supposed that vege- 
tation filtered the miasm from the air. It was argued that if 
air vitiated by respiration be confined in a bottle containing 
a living plant and exposed to the rays of the sun, the carbonic- 
acid gas will be absorbed and the air restored to its original 
condition, plant life consuming carbon dioxide and exhaling 
oxygen. So firm was this belief that in the days of ancient 
Rome trees were protected by law. 

It is needless to say that the protective power of living 
plants was as much overestimated as the faculty of decaying 
vegetation, to cause malaria. Their power of absorbing moist- 
ure from the soil is more than outweighed by the shade they 
afford the ground. 

While the clearing of land of trees and vegetation may be 
followed by an outbreak of malaria, this may be due to the 
overturning of the soil, which usually goes hand in hand with 
opening land, and to the hardships attending such labor. The 
ultimate effect of clearing trees from the land is to diminish 
malaria by permitting the sun to dry the soil. 

If trees have any protective virtue whatever it is probably 
through affording shelter and food for mosquitoes. The cul- 
ture of eucalyptus trees is now known to have no prophylactic 
effect upon malaria. 

Weeds and other vegetation growing in the water favor 
the development of mosquito larvae by protecting the surface 
of the water from agitation by the wind. 

Vegetable decomposition bears no relation to the etiology 
of malaria other than as an index to heat and moisture. 

Wind. — The wind was formerly held responsible for trans- 
mitting malaria long distances. It was believed that the mala- 
ria of Edinburgh was imported by the winds from Holland, 
and that Italy became malarious through the agency of the 
African sirocco. The land breezes, especially if they blew 



ETIOLOGY 49 

over marshy areas, were regarded as more highly noxious 
than the sea breezes. 

As a matter of fact, the wind has little or no power to 
transmit malaria for distances of any consequence. While 
it is theoretically possible for infected mosquitoes to be borne 
by the wind, in reality these insects, especially the anopheles, 
being weak fliers, seek shelter while a breeze is blowing. 
The immunity from mosquito bites afforded by the Indian 
punkah, or a common fan, is evidence of this. 

Furthermore, the disturbing effect of the wind upon the 
surface of the water interferes with oviposition of the adults 
and with respiration of larvae and pupae. 

Exposure to cold winds may have the effect of arousing 
latent malaria. An incident related by Watson 72 is a striking 
illustration. Thirty ladies and gentlemen had sailed to the 
mouth of the Tiber on an excursion of pleasure. Suddenly 
the breeze shifted to the south and began to blow over a 
marshy tract of land situated to windward of them. Twenty- 
nine of the thirty were immediately after attacked with tertian 
ague. 

The occurrence of malaria upon shipboard has been cited 
as an argument that malaria is an air-borne disease. Bilge 
water in the holds of vessels has also been accredited with 
producing malaria at sea. The dangers of malaria from car- 
goes of sugar and fruits were recognized by old writers. 

Malaria occurring upon ships may be accounted for in sev- 
eral ways. These cases may be manifestations of malaria 
contracted upon shore. Even cases occurring long after em- 
barking may be explosions of latent malaria. If vessels anchor 
too close inshore in malarial regions infected mosquitoes may 
easily gain access to the crew — a half mile from shore is 
probably a safe distance. It has been proven that mosquitoes 
may be carried for considerable periods in the holds and sleep- 
ing apartments of ships. 

Commercial vessels are more apt to carry mosquitoes than 
are warships, through loading and unloading of cargoes. 

There are many places where, notwithstanding apparently 
favorable topographic and meteorologic conditions, malaria is 

4 



50 THE STUDY OF MALARIA 

entirely absent. This is due to the absence of either malaria- 
bearing mosquitoes, or malarial parasites, or of both. Among 
a number of such places may be mentioned the city of Rome 
and other portions of Italy, Madeira, portions of Cameroon, 
Chole Island, Comoro Island, Rodriquez Island, the Sey- 
chelles Islands, portions of India and of Borneo, the French 
Islands, Ponape, Saipan, Samoa, New Caledonia, Tahiti, Bar- 
badoes, and portions of Brazil and of the Argentine Republic. 
The majority of such localities are islands and in the southern 
hemisphere. 

Race ; Immunity. — Certain protozoan diseases among lower 
animals confer immunity. In the Texas fever of cattle an 
attack, if recovered from, is followed by immunity. There 
are said to be breeds of cattle naturally immune to the disease. 
In the large game animals of Africa one infection with try- 
panosoma brucei confers immunity. Koch found that birds 
that had been infected with proteosoma grassii could not be re- 
infected. 

From analogy it might therefore be expected that immunity 
to malaria might exist with some individuals or races. This 
is true, however, in only a limited sense. 

While the various races of mankind vary somewhat in sus- 
ceptibility to malaria none can be said to possess absolute 
immunity. 

Caucasians residing in non-malarial countries are, when 
exposed, most liable to contract malaria. Negroes bred in 
highly malarial regions are, as long as they remain upon the 
native soil, least susceptible to paludal infection. 

Immunity within the race increases generally as we go to- 
ward the equator. Thus the negroes of the Southern States 
display less immunity than the negroes of the West Indies or 
of tropic Africa. Likewise it may be said that immunity is 
much more marked in countries with a high than in those 
with a low, endemic index. 

The immunity of the negro race has been variously esti- 
mated, some observers maintaining that they are absolutely 
proof against malarial invasion, while others hold that they 
are as susceptible as the whites. The truth lies between these 



ETIOLOGY 51 

two extremes. Adult negroes reared in malarial regions are 
much less liable to paludism, as long as they remain indigenous, 
than are the whites. The negro race does not, however, enjoy 
an absolute but only a relative immunity from malaria. 

According to Sternberg, 73 there were in the Department of 
Texas of the United States Army during the year ending June 
30, 1883, among the white soldiers 21.36 per cent; colored, 
6.27 per cent., of periodic fevers to all kinds of fevers. 

In 1845 m °st of the Europeans aboard the steamer L'Eclair, 
stationed upon the coast of Africa, died of malarial fever, 
while none of the forty Kroo negroes who were members of 
the crew were attacked. 

In the hospitals of St. Louis and of Goree, among 100 Euro- 
pean patients 36 have malaria, while of 100 black patients 
only 9 have malaria. 1 

The medical statistics of the French colonial troops for the 
year 1903 give the following figures for French West Africa: 
European troops, malarial morbidity, 690; mortality, 7.5 per 
thousand of effective force; negro troops, malarial morbidity, 
12.45 5 mortality, 0.3 per thousand. 

The following table from La Roche 74 will show the com- 
parative ratio of mortality from the disease per thousand of 
mean strength in various commands of the British Army: 

Whites. Blacks. 

Windward and Leeward Islands 36.9 4.6 

Jamaica 101.9 8.2 

Bahamas 159.1 5.6 

Honduras 81.0 4.4 

Sierra Leone 410.2 2.4 

Mauritius 1.7 0.0 

Ceylon 25.7 1.1 

Sternberg 73 gives the ratio per thousand of mortality from 

malarial diseases in the United States Army thus : 

1868. 1869. 1870. 

White 94.20 140.67 72.99 

Colored 74.62 15.62 38.46 

From a compilation of the mortality statistics for the years 
1852-1866 in Guiana, Maurel 75 gives the following results: 

Number of Deaths. Ratio. 

Europeans 12,819 12.00 

Arabs 1,112 8.54 

Negroes 1,172 5.75 



52 THE STUDY OF MALARIA 

According to Hirsch, 18 there died of malarial fevers per 

thousand of population in Ceylon: 

Negroes , i.i 

Indians 4.5 

Malays 6.7 

Singalese 7.0 

English 24.6 

During the Civil War both the morbidity and mortality 
from malaria in the negro race were greater than in the white 
race. However, the negro soldiers are said to have been 
more exposed to malaria than the whites, having been aggre- 
gated in malarial localities. 76 

With the better hygienic surroundings and more limited 
exposure of the whites the negroes would probably be attacked 
less often than they are. Whether the color, thickness, or 
other qualities of the skin of this race have anything to do 
with their relative immunity is not known. 

The Chinese are said to be very susceptible to malarial 
infection. The Arabians and the Siamese are almost as fre- 
quently and as gravely attacked as the Europeans. 

Laveran 1 states that it is difficult to estimate exactly the 
relative frequence of malarial fevers in the Europeans and in 
the Algerians, since the latter often escape observation, but 
he believes the natives have a degree of resistance and of 
tolerance not possessed by the Europeans. 

The disease is said to be relatively rare in the natives of 
Madagascar. Adult Filipinos are more frequently attacked 
than the African negroes. The Abyssinians are often in- 
fected. The Malays, Javanese, and Tamils are much less 
susceptible than the Caucasians. 

At Stephansort Koch 42 found various races infected in the 
following proportions: 

Number of Per- Number infected p p poi- 
sons Examined. with Malaria. 

Europeans 21 12 57.1 

Chinese 240 63 26.3 

Malays 209 53 25.3 

Melanesians 264 29 10.9 

Total "734 T57 214 

Immunity from malaria is probably an acquired immunity 
in the great majority of instances, though the contrary opinion 



ETIOLOGY 53 

is held by some competent authorities upon the subject. The 
reasons for believing that this immunity is acquired by re- 
peated infection, especially in childhood, and by prolonged 
residence in a malarial region, a sort of acclimatization, are 
that immunity is much more prevalent in adults than in chil- 
dren; that immunity is often diminished by a change of resi- 
dence, or may be entirely lost by a temporary residence in a 
non-malarial climate ; and that immunity in an individual may 
exist toward one form of malaria and not toward others. 

That immunity is much more manifest in adults than in 
children is evident from the consideration of the endemic 
index of a malarial region, particularly of countries where the 
latter is high. During the first years of life many individuals 
examined show evidence of malarial infection, older children 
in a less proportion, and adults evince a relative immunity. 
This would hardly be the case if the immunity were racial 
and congenital. 

The effect of a change of residence upon malarial immunity 
is a well-known fact. Plehn 5 says that the Soudan negroes, 
relatively immune at home, are often afflicted with malaria 
when going as soldiers to other parts of the continent. Smith 77 
states that, while the native negroes of Sierra Leone are in- 
frequently attacked, and only with mild degrees of malaria, 
in the West Indies regiment of negroes stationed in Sierra 
Leone the fever is of a very severe and often fatal character. 

Individuals once immune to malaria may become susceptible 
on returning home from a temporary residence in a malaria- 
free country. Plehn 5 mentions three Cameroon negroes who, 
shortly after returning from a several years' sojourn in Eu- 
rope, were attacked with severe remittent fever. 

Repeated infection and consequent immunity to one form 
of malaria does not usually protect the individual from the 
other forms. Koch 78 found certain islands among the Bis- 
marck Archipelago where quartan fever alone was endemic. 
Laborers from these islands sickened readily with tertian and 
estivo-autumnal malaria in Stephensort. Elting 79 has shown 
that persons who could not be artificially inoculated with a 
certain variety of the parasite could be with another. 



54 THE STUDY OF MALARIA 

In the South there is little difference between the races as 
regards susceptibility to the various forms of malarial infec- 
tion — tertian, quartan, and estivo-autumnal. Clinically, how- 
ever, pernicious cases, cachexia and hemoglobinuric fever, are 
rarer in the negro. 

Instances of cachexia followed by immunity have been ob- 
served, especially by the Italian school. In these cases, after 
recession of the spleen and liver, and restoration of the blood 
elements, a stable immunity resulted. Subjects of existing 
cachexia, even though free from clinic evidences of acute 
malaria for years, can hardly be regarded as immune. 

Rarely are persons encountered in highly malarial localities 
who have never been attacked with malaria. Such persons are 
supposed to possess congenital immunity. Celli 80 obtained pre- 
cise histories of four persons living in the Pontine Marshes 
who were absolutely immune, having never had malaria, 
though they took no prophylactic precautions ; their color was 
good, and their livers and spleens normal. In persons claim- 
ing never to have had malaria allowances must be made for 
the possibility of unrecognized attacks, especially in early child- 
hood, which might give rise to an acquired immunity. 

In conclusion, the resistance of the black race to malaria 
is due to repeated attacks in early childhood, and not to any 
great extent to heredity. While in a sense natural selection 
is a factor, it is largely an individual struggle, the selection 
of the fittest occurring in infancy, and but little being derived 
from progenitors. 

Sex. — As a general rule, females are less often attacked 
with malaria than males, though in childhood the proportion 
is about even. 

That women are less frequently infected is not due to a 
higher degree of resistance, but to the fact that they are less 
often exposed and are more temperate in their habits. It is 
probable that if they were equally exposed with males they 
would be even more often infected than the latter, on account 
of the greater delicacy of the skin and the manner of dress. 

In certain localities women are not less frequently attacked 
than men. In Panama there is said to be very little, if any, 



ETIOLOGY 55 



difference between the sexes in this respect. 30 In the Dutch 
East Indies European women are more susceptible than men. 81 - 
Davidson 66 says that from 1871-75 the death rate of soldiers' 
wives in India was 4.20 per thousand, as compared with 2.81 
for the men; and that in Bombay, 1885-86, the female death 
rate was 10.14; that of males, 7.56. 

The following are some figures showing the sex distribution 
in a few localities : 

Males. Females. 

Stephansort 42 32 21 

Alabama 74 585 451 

Italy 82 312 327 

Italy 83 311 236 

Bulgaria 36 1,742 995 

Italy 84 268 147 

Greece 68 1,202 972 

Baltimore 29 493 121 

Total , 4,945 3,270 

In an institution in Alabama Simms and Warwick 85 found 
among deaf mutes 1.05 per cent, of the males and 6 per cent, 
of the females infected ; among blind, 6 per cent, of the males 
and 3 per cent, of the females. 

Pregnant women are probably less often infected because, 
on account of their condition, they are less often exposed; 
when exposed they are very susceptible. The puerperium pre- 
disposes to malaria. 

Age. — Children are more frequently and more severely af- 
flicted with malaria than adults. This is probably due to their 
more delicate skin, their manner of dress, sounder and more 
prolonged sleep, and inability to defend themselves against 
mosquito bites. The fact that cases of malaria in children 
more often escape correct diagnosis may account somewhat 
for the greater frequency, especially of relapses. 

The subjoined figures show the distribution of malaria 
according to age : 

Age 0-10 10-20 20-30 30-40 40-50 50-60 60-70 70-80 80-90 

Thayer and Hewet- 

son 29 18 146 204 130 65 36 11 3 1 

Rogers 86 2 13 10 3 

Cardamatis 68 729 499 398 230 144 100 55 15 3 

Conti 82 245 146 83 61 63 _^^ ... ^^ _ LJL1 

Total 994 804 695 424 272 136 66 18 4 



56 



THE STUDY OF MALARIA 



Of 2,073 malarial subjects observed by De Brun 86 at Beirut 
1,065 were children and under eight years of age. 

Of 1,784 cases recorded by Hope, 40 862 were in children 
under fifteen and 922 in persons of fifteen or over. 

Malaria causes a greater number of deaths in children than 
among adults. Strachan 87 tabulates 2,377 deaths from malaria, 
of which 1,428 occurred in children under one year of age, 
275 from one to five years of age, 157 from five to twenty, 
and 517 from twenty to seventy-five years of age. 

The following figures show the percentage mortality of 
malaria, according to age, compiled from the table of Savas 68 
in Greece: 



0-5 Years. 
54 



5-10 Years. 
10 



10-20 Years. 

8 



20-40 Years. 
II 



40-60 Years. 

9 



60-80 Years. 

8 



Endemic Index. — The percentage of children infected in a 
given locality is the index to the prevalence of malaria in that 
region (Fig. 5). As Ross 88 expresses it, "There is probably 




Fig. 6.— Spleen rate in British Central Africa (after Daniels). 



only one really accurate method by which we can determine 
the degree of malaria in a given locality, and that is by ascer- 
taining the average time in which a newcomer becomes in- 
fected. The shorter this period the greater, evidently, the 




Fig. 5. — This group shows a high Index endemicus. 



ETIOLOGY 57 

malaria potential of the locality. Native children constitute the 
class of newcomers most accessible for making the estimate." 

The most accurate method of determining the index en- 
demicus of an area is to make a large number of blood 
examinations of native children at various ages. This requires 
a great deal of time. It has been repeatedly shown that in 
regions where malaria prevails extensively a large per cent. 
of young children harbor the parasites without manifesting 
any symptoms of the disease, the index decreasing as the 
age increases. For this reason young natives with latent 
malaria are the source of the greatest danger to the com- 
munity. 

Koch 78 records the following indices: 

At Bogadjim: Per Cent. Infected. 

Children under two years 80.0 

Children from two to five years 41.6 

Persons over five years 

At BongU : Per Cent. Infected. 

Children under two years 100.0 

Children from two to five years 46.1 

Children from five to ten years 23.5 

Persons over ten years 

Panse's 89 observations at Tanga may be tabulated thus : 

Per Cent. Infected. 

Children under one year 48.0 

Children from one to three years 87.6 

Children from four to seven years 65.1 

Older children and youths 39.4 

Adults 15.3 

Similar results were noted by Schaudinn 90 in San Michele 
di Leme : 

1901. Per Cent. Infected. 

Children under five years 100.0 

Children from five to ten years 83.0 

Children from ten to fifteen years 100.0 

Persons from fifteen to sixty years 

1902. Per Cent. Infected. 

Children under five years 100.0 

Children from five to ten years 100.0 

Children from ten to fifteen years 83.0 

Persons from fifteen to sixty years J. 7 

Annett, Dutton and Elliott, 91, in Nigeria, obtained the results 
recorded in the following tabulation: 



58 THE STUDY OF MALARIA 

Age. Per Cent. Infected. 

Under one year 27.3 

From one to two years 63.0 

From two to three years 63.0 

From three to four years 51.0 

From four to five years 48.8 

From five to six years 38.8 

From six to seven years 6.6 

From seven to eight years 27.5 

From eight to nine years 25.0 

From nine to ten years 14.0 

Ten years and over 10.0 

Craig 91 reports the endemic index about Camp Stotsenburg 
as follows : 

Per Cent. 

From one to five years 72.5 

From five to ten years 37.0 

From ten to fifteen years 24.5 

In calculating the endemic index a sufficiently large number 
of persons should be examined in order to eliminate error. 
It has been estimated that if fifty persons be examined and the 
blood of twenty-five found to contain parasites, the margin 
of error being 20 per cent., the index would not be 50 per 
cent., but between 30 and 70 per cent. Furthermore, while a 
high index indicates widespread malaria, an index of zero 
must not be construed to indicate an entire absence of the 
disease, since experience has shown that it may exist where 
the index, estimated in this manner, is zero. 

In comparing the indices of two localities the figures should 
be taken at corresponding seasons, since the index of a given 
locality varies according to season. Thus Rogers 4 * observed 
in the tea gardens of Assam that the endemic index reached 
80 per cent, in October, but was only 30 per cent, in the same 
place early in April. Laveran 1 states that, while the endemic 
index of a certain portion of Java was 57.5 per cent, in Janu- 
ary, it fell to 32 per cent, in May. 

The prevalence of splenic enlargement has been employed 
to calculate the extent of paludism, this method requiring 
much less time than the examination of the blood. Among 
unhealthy villages of Borneo, Nieuwenhuis 86 found the spleen 
enlarged in 80 per cent, of the children examined. Schellong 92 
found the spleen index at Finschhafen to be 84 per cent. An 



ETIOLOGY 59 

examination of the school children held at Marathon in Octo- 
ber, 1906, showed that enlargement of the spleen was to be 
found in every pupil. 93 

The spleen rate and the endemic index, estimated by a micro- 
scopic examination of the blood, do not usually correspond 
even approximately. In Algeria the Sergents 86 found the 
spleen rate in children from one to five years old to be 63.58 
per cent., while the parasite rate was only 18.18 per cent. 
Stephens and Christophers 94 have prepared the following table 
to illustrate the relation between the spleen rate and the 
parasite rate : 

Locality. Spleen Rate. Endemic Index. 

Calcutta 0.0 0.0 

Jalpaiguri — 

Bustee children 27.0 16.1 

School children 14.7 0.0 

Babu children 14.2 0.0 

Mainaguri 74.0 25.0 

Rungamutty *. 83.0 43.6 

Sam Sing 7.1 16.0 

Kurseong I O.o O.O 

Kurseong II 0.2 0.0 

These investigators draw the following conclusions : 

1. A high endemic index may exist without any appreciable 
spleen rate (Africa). 

2. A high spleen rate may exist in adults without a corre- 
sponding parasite infection. 

3. In India (Bengal) among children a high spleen rate is 
a fair indication of the parasite infection. 

4. The spleen rate, unlike the parasite rate, increases up 
to a certain age limit and may be considerable when the para- 
site rate is nil. 

The writer does not believe that the spleen rate would dis- 
close the true endemic index of regions in the Southern States. 

Length of Residence. — In highly malarial regions, espe- 
cially in the tropics, newcomers are usually infected during the 
first year. Craig 70 says that of the hundreds of cases of 
malaria occurring in our soldiers in Cuba almost 95 per cent, 
gave a history of being there from two to six weeks before 
the onset of the disease, and that one month was the period 
most commonly given. 



60 THE STUDY OF MALARIA 

In the Southern States the period before infection varies 
greatly according to circumstances. Newcomers who live in 
hygienic surroundings, and who observe ordinary precautions, 
may go for years without developing the disease. On the other 
hand, persons coming South who take no precautions, and 
who expose themselves carelessly, are liable to be attacked 
early. Thus, it is said that when the Beaumont oil fields were 
opened up people flocked there from nearly every section of 
the country, and nearly every newcomer was struck down 
within a few weeks with malarial fever in some form. 

Residence, even prolonged, in a malarial locality does not 
confer absolute immunity to malaria. . 

Change of Residence. — The effect of a change of residence 
upon the immunity in the negro race has been referred to. 

It is a common observation that moving to another locality 
"brings the malaria out of the system." This malaria is 
usually latent — always so, of course, if the new residence is 
in a non-malarial region. It is not uncommon for persons 
who have never had recognizable paroxysms to suffer an out- 
break upon leaving the endemic region. 

Occupation. — This is a factor in the etiology of malaria 
in two respects : first, by reason of certain occupations exposing 
the person to the bites of mosquitoes; second, by reason of 
the exposure and exertion attending certain occupations awak- 
ening latent malaria. 

Rural avocations more commonly expose to malaria than 
urban. Occupations which necessitate residence at highly 
malarious spots are especially dangerous, as well as those that 
require being out of doors at night. 

Overturning the soil, as in gardening, farming, ditching, 
railroad, levee, and canal construction, predisposes to malarial 
infection. Fishermen, soldiers, night-watchmen, engineers, 
and timber-workers are often exposed. 

Rice culture, requiring as it does the retention of water 
from the surface of the ground, is not an unalloyed boon as 
an innovation into many of our Southern States. The dangers 
to the community from the growth of rice were recognized 
many decades ago near Savannah and Charleston. Malaria 



Hi 




»■& 



Fig. 7. — Exposure to the sun is one of the predisposing causes of malaria. 



ETIOLOGY 6l 

is said to have almost disappeared from the regions of Parma 
and Vincenza when rice culture was discontinued. 

Social Condition. Civilization. — Formerly malaria at- 
tacked all classes. Many noted persons were frequently in- 
fected, and James I and Cromwell died of the disease. Moats 
and lakes near castles and country estates were doubtless to 
blame. 

Now malaria is chiefly a disease of the poor and ignorant 
classes. The man in the well-constructed and properly- 
screened residence is much less liable to become infected than 
the one in the loosely built and unprotected hut. The occupa- 
tions and food of the poorer classes are also factors in the 
greater prevalence among them. 

Persons living in cities and towns are much less apt to be 
exposed to infection than those in villages and in the country. 
Many towns and cities in the heart of malarial areas are rela- 
tively free from the disease. Suburbs are more highly mala- 
rious than the more dense populated sections, for the reason 
that the mosquito has more opportunity to breed in the former. 

Other Factors. — There are certain factors of the utmost 
importance in the etiology of malaria, and before the truth 
was known were looked upon as causing the disease. These 
are overwork, fatigue, exposure to sun, rain, and cold, excesses 
in Bacchus and in Venus, psychic emotions, loss of sleep, trau- 
matism, surgical intervention, overeating, hunger, thirst, diges- 
tive disorders, menstruation, parturition, intercurrent affec- 
tions, and the administration of certain medicaments. 

Watermelons, muscadines, cucumbers, and other articles 
have yet the reputation in parts of the South of causing chills. 

The administration of tuberculin and of potassium iodide 
are said to be followed not infrequently by outbursts of 
malaria. 

It is obvious that the influence of these factors is upon latent 
malaria, or the parthenogenetic cycle of the parasite's life his- 
tory. 

Insufficient and improper food both lowers the resistance 
to new infections and kindles latent malaria into activity. 



62 THE STUDY OF MALARIA 

The effect of deficient nourishment upon malaria mortality 
is well illustrated by the following table, compiled by Roux 
from statistics in India, where rice is the staple food of the 
lower classes : 

Year. Price of Rice. Deaths from Malaria. 

1874 2 rupees 4 891 

1875 2 rupees 9 842 

1876 2 rupees 12 902 

1877 3 rupees 12 991 

1878 4 rupees 8 1,002 • 

While the major portion of many older works on malaria 
was devoted to the role of drinking water in the contagion of 
malaria, it is now known that it is of minor importance. 

Celli 67 had several healthy individuals, in the San Spirito 
Hospital of Rome, to drink for a number of days water 
obtained from the Pontine marshes and from stagnant pools. 
The results were uniformly negative. 

Zeri 67 conducted three series of experiments with water 
from malarious localities: 1. He had nine individuals drink 
from I/2 to3 litres of water daily from five to twenty days, 
each person consuming from 10 to 60 litres of the water. 2. In 
sixteen individuals the mucous membranes of the respiratory 
tract were sprayed with marsh water by means of a com- 
pressed-air atomizer. 3. In five persons water from malarial 
places was injected into the rectum. The results of all these 
experiments were negative. 

It has been maintained that water in which mosquitoes har- 
boring parasites have died is capable of producing malaria. 
This is based upon the single experiment of Ross, who had 
an Indian native drink a small quantity of water in which 
there were dead mosquitoes which had fed upon malarial 
blood. Eleven days later the native developed fever which 
terminated spontaneously after three days without relapsing. 
In the blood were found ring forms of the estivo-autumnal 
parasite. This experiment was repeated, but the result could 
not be confirmed, so must be regarded as co-incidental. 

In regard to the immunity to malaria enjoyed by opium- 
eaters, Russell 95 states that the observations of several sur- 



ETIOLOGY 63 

geons of extensive experience in opium-eating regions confirm 
the popular belief that the opium-eater, in the early stages of 
the habit, while as yet not constitutionally broken by its long 
continuance, does, as a matter of fact, enjoy considerable 
immunity from malarial affections. This writer concludes that 
this power of opium is partially responsible for its prevalence 
in some of the eastern countries. Moore 15 testifies also that 
opium-smokers are more resistant to malaria. 

Epidemics. — Malaria, known as an endemic disease, occa- 
sionally prevails so intensely as to acquire the dignity of an 
epidemic. Becoming more frequent and fatal in its native 
haunts, it may spread to regions ordinarily immune, and may 
even assume the extent of a pandemic. 

The first pandemic of which we have any knowledge oc- 
curred in 1557 to 1558, and is said to have overspread all 
of Europe. The next appeared from 1678 to 1682, and was 
nearly as extensive as the former. Similar epidemics arose 
during 1718-1722, 1748-1750, 1770-1772, and 1779-1783. 
During the past century an epidemic occurred from 1806 to 
1812, and one from 1823 to 1827 is said by Hirsch 18 to have 
been one of the most extensive, severe, and persistent of pan- 
demics, of which reports were received from almost all parts 
of the world. Between 1845 an d 1849 an d 1855 and i860 
malaria assumed epidemic form, and the great pandemic of 
1866 to 1872 marked the invasion of Mauritius and Reunion, 
where malaria was previously unknown. 

Quite recently epidemics of malaria have been reported in 
Algiers, Greece, and elsewhere. 

What may be called house epidemics or domestic epidemics 
are common in the experience of many observers. 

It is well known that the residents of certain houses suffer 
much from malaria, and that certain houses are seldom free 
from the disease during the malarial season. For this local 
conditions are responsible. 

The writer has more than once seen as many as half a 
dozen cases in one family at the same time, and in many fami- 
lies every member is successively attacked during the season. 

Modes of Infection. — The only known modes of transmis- 



64 THE STUDY OF MALARIA 

sion of malaria necessary to consider are: i, congenital; 2, 
artificial inoculation, and 3, inoculation through the bites of 
certain species of mosquitoes. 

Congenital Malaria. — It was formerly believed that malaria 
was not infrequently transferred from mother to fetus. 
Ducheck 96 published a case, in 1858, of a child whose mother 
suffered from malarial paroxysms during pregnancy. The 
child dying three hours after birth, at autopsy the liver and 
spleen were found to be enlarged, and the spleen and blood 
of the portal vein contained considerable pigment. 

Two cases are reported by Felkin. 97 In the first case the 
diagnosis was based upon intrauterine quivering of the fetus, 
enlarged spleen at birth, and fever later, the date of which is 
not recorded. In the second case the mother had never had 
malaria, having never been outside of Edinburgh, but the 
infection is attributed to the father, who had contracted mala- 
ria in Africa several years previously and, as Felkin believes, 
had transmitted the disease to no less than three infants. 

Watson 72 cites the case of a woman who was suffering with 
tertian ague. On alternate days when she missed the parox- 
ysms she could feel the child shiver with chills. Bark was 
prescribed and the paroxysms of the fetus were first inter- 
rupted, then those of the mother. 

However, of numerous cases recorded by a score or more 
of early writers, all are open to two objections: First, the 
diagnosis was not certainly established; secondly, postnatal 
infection was not excluded. 

Marchiafava and Bignami 22 mention four cases in which 
the blood of the fetuses of malarial mothers was entirely 
negative. 

Thayer 98 records a case of a negress who had had malaria 
at least five months and whose blood contained three groups 
of the quartan parasites when she gave birth, during a 
paroxysm, to a child whose blood, upon repeated examination, 
was found free from parasites and pigment. While both para- 
sites and pigment were found upon the maternal side of the 
placenta, none was found upon the fetal side. 

Sereni, 86 who examined the blood of four infants born of 



ETIOLOGY 65 

malarial mothers, was unable to find evidences of malaria in 
any case. 

Ziemann, 4S likewise, in four cases of new-born children of 
malarial infected mothers, had uniformly negative results. 

The writer has upon several occasions obtained blood from 
infants, immediately after birth, whose mothers harbored 
malarial parasites, and in no case have parasites been detected. 
Similar results have been obtained by Bastianelli, 22 Caccini, 22 
Borne, 90 Schoo, 90 F. Plehn, 5 Terburgh, 79 A. Plehn," Wellman, 68 
and others. 

Pezopoulos and Cardamatis 100 based the following conclu- 
sions upon six cases, five full-term labors and one abortion, 
which they studied. 

1. In the blood of the six mothers there were parasites, 
more or less abundant. 

2. In the blood of the new-born and of the aborted fcetus, 
examined a few hours after expulsion, there were no parasites. 

3. In the blood of the liver and spleen, as well as in sections 
of these organs of the two fetuses which were examined 
postmortem, no parasites were found. 

4. In the blood taken from the maternal surface of the 
placentae of the five new-born children there were parasites in 
abundance, while in the blood taken from the fetal surface 
there were no parasites, or at most a very few. 

5. In blood taken from the umbilical cord no parasites were 
found. 

6. In the blood of the placenta of the aborted fetus no 
parasites could be detected. 

Bein and Kohlstock 101 are said to have found malarial para- 
sites in the blood of a four-months-old child born sometime 
after the arrival of the mother in a region free from malaria. 

Winslow 102 records a case which he believes to be congenital, 
though the parasites were not detected until the child was 
eleven weeks old. 

A case of malarial fever in infancy thought to be maternal 
in origin is reported by Peters. 103 The examination of the 
blood on the second and third days after birth was negative, 
though parasites were found on the fifty-first day. 



66 THE STUDY OF MALARIA 

Moff att 104 observed a case supposed to be congenital malaria, 
though the parasites were not detected before the seventh 
week. 

Bouzian, 105 in Algeria, detected parasites in the blood of an 
infant only twelve days old. 

Hitte 106 collected from the literature 21 cases of malaria 
considered congenital. In 13 of these the blood was not 
examined; in 1 parasites were detected four months after 
birth, and in 5 cases parasites were found from several weeks 
to two months after birth. The remaining 2 cases were ob- 
served by Hitte personally, who claims to have found parasites 
in the blood obtained from the umbilical cords. The mothers 
of both children were suffering with malaria. 

Parasites were found by Simms and Warwick 85 in the blood 
of three babies between three and seven days old ; the mothers 
had previously had malarial paroxysms. 

Holt 107 mentions a case in which he states there seems little 
doubt that the disease was contracted in utero. The mother 
had been suffering with tertian intermittent. Eighteen hours 
after birth the child showed evidences of a malarial paroxysm. 
The next day malarial organisms were found in the blood. 

Economous 1108 reports 6 cases with almost conclusive evi- 
dence of congenital origin. In each of these cases the blood, 
examined from eight to forty-eight hours after birth, con- 
tained malarial parasites. The mothers had, previous to deliv- 
ery, suffered with malaria. 

Bel 109 mentions a female patient who died of pernicious 
malaria. The parasite was found in the blood, pericardium, 
meninges, and spleen, as well as in a seven-months fetus. 

As may be inferred, properly proven cases of congenital 
malaria are rare. This reluctance of the parasites to pass 
through the placenta is in keeping with their aversion to leave 
the blood-vessels. It has been pointed out that no parasites 
are found in the hemorrhages and perivascular exudates in 
cases of pernicious malaria, though they may exist in hordes 
within the vessels. . Congenital malaria is probably to be ex- 
plained in the majority of cases through placental lesions 
permitting direct mingling of maternal and fetal blood during 
parturition. 



ETIOLOGY 67 

Inoculation. — Even before the parasite of malaria was dis- 
covered Gerhardt 110 succeeded, employing the blood of mala- 
rial subjects, in inoculating healthy persons with malaria. 

Since then many similar experiments have been performed. 
Tertian malaria has been transmitted by inoculation by Bein, 
Bacelli, Antolisei and Angelini, Mannaberg, Elting, and others ; 
quartan by Gualdi and Antolisei, Di Mattei, Calandruccio, 
Bacelli, and Celli and Santori; estivo-autumnal by Gualdi and 
Antolisei, Di Mattei, Celli and Santori, Bastianelli and Big- 
nami, and Elting. 

The injection of blood containing only crescents gave nega- 
tive results in the experiments of Thayer, Bastianelli, Big- 
nami, and Elting. Di Mattei and Calandruccio, however, 
observed an irregular form of fever to follow such an injec- 
tion. This can be explained only by parthenogenesis. 

The injection of blood containing a certain species of para- 
sites is followed by fever characteristic of that species, and 
these parasites are to be found in the blood of the person 
inoculated. 

There are only two experiments which, at first sight, seem 
to contradict this specificity of the different parasites. These 
were performed by Gualdi and Antolisei. Blood from two 
patients suffering with quartan malaria was inoculated into 
two healthy persons. In one case the injection was followed 
in ten days by irregular fever and estivo-autumnal parasites 
were detected in the blood. In the other case after twelve 
days an irregular fever began and estivo-autumnal and a few 
quartan parasites were found in the blood. It was later dis- 
covered that the patients from whom the blood was taken 
had recently suffered with quotidian, tertian, quartan, and 
irregular fever, hence it is evident that a pure culture of 
quartan parasites was not obtained. These same observers, in 
subsequent experiments, found that the injection of one species 
of parasite was followed by the characteristic fever and the 
appearance of the same species of parasites in the blood of 
the person inoculated. 

There are those who cannot be successfully inoculated with 
one species of parasite but can with another. It has been 



68 THE STUDY OF MALARIA 

shown also that one species of parasite often disappears from 
the blood upon inoculation with a different species. Di Mattei 
found that the inoculation with estivo-autumnal parasites of a 
patient already infected with quartan malaria caused a disap- 
pearance of the quartan and a development of the estivo- 
autumnal parasites, and that the inoculation with quartan 
parasites of a patient already infected with estivo-autumnal 
caused a disappearance of the latter and a development of 
the quartan parasites. 

The degree of development of the parasites apparently has 
no effect upon the result, since the disease develops as readily 
after the injection of blood containing adult organisms as 
after that containing young parasites. It is immaterial also 
whether the blood be injected intravenously or subcutaneously. 
A very small amount of blood, even less than one drop, is 
often sufficient for inoculation. 

The injection of defibrinated blood, of centrifugalized cor- 
puscles, and of blood diluted with an equal quantity of dis- 
tilled water and inoculated immediately have given positive 
results. The injection of dissolved dried blood, and blood 
diluted with an equal quantity of distilled water and allowed 
to stand an hour, have proven negative. 

Jeffries 111 reports the case of a New York surgeon who had 
never had malaria supposed to have contracted the disease by 
pricking his finger several times during an operation upon a 
woman infected with malaria. Sixteen days after the opera- 
tion the surgeon had the first chill and had several subse- 
quently. The blood contained many estivo-autumnal para- 
sites. 

Dochmann 86 attempted to inoculate malaria from man to 
man by means of the serum from a herpetic vesicle. While 
he claims to have succeeded, the results of his experiments 
have never been confirmed. 

Efforts to inoculate the lower animals with human malaria 
have been fruitless. Such attempts have been made upon 
horses, mules, dogs, monkeys, rabbits, mice, guinea-pigs, 
hedge-hogs, bats, wolves, cats, pigeons, doves, magpies, 
screech-owls, turtles, frogs, and lizards. 



ETIOLOGY 



69 



DISSEMINATION OF MALARIA BY MOSQUITOES 

The discovery by Ross of the role of the mosquito in the 
dissemination of malaria is the most startling achievement of 
modern medical science. 

Mosquitoes do not cause malaria; they carry it from in- 
fected to healthy persons. The parasites, sucked with blood 
from a malarial individual, undergo a cycle of development 
within the body of the mosquito, and are then inoculated into 
healthy persons. Man is merely the intermediate host of the 
parasite, the mosquito is the definitive host, and it has been 
said that man gives malaria to the mosquito, and not the 
mosquito to man. 

Not all species of mosquitoes can serve as hosts for the 
malarial parasite. It is only certain members of the sub- 
family Anophelince that have been found to act in this capa- 
city. Of this subfamily the following have been determined, 
with more or less certainty, to be malaria carriers: 



Anopheles annulipes. 
Anopheles bifurcatus. 
Anopheles cohacsus. 
Anopheles crucians. , 
Anopheles farauti. 
Anopheles fluvialis. 
Anopheles jormoscensis. 
Anopheles maculipennis. 
Anopheles martini. 
Anopheles punctipennis. 
Anopheles pursati. 
Anopheles vagus. 
Anopheles vincenti. 
Cellia albipes. 
Cellia ar gyro tarsus. 
Cellia pharcensis. 
Myzomyia Christophersi. 
Myzomyia culicifacies. 
Myzomyia funesta. 
Myzomyia Hispaniola. 
Myzomyia Listoni. 



Myzomyia Ludlowii. 
Myzomyia Lutzii. 
Myzomyia picta. 
Myzomyia Rossii. 
Myzomyia Turkhudi. 
Myzorhynchus barbirostris. 
Myzorhynchus Coustani. 
Myzorhynchus paludis. 
Myzorhynchus sinensis. 
Myzorhynchus Ziemanni. 
Nyssorhynchus fuliginosus. 
Nyssorhynchus Jamesii. 
Nyssorhynchus macidatus. 
Nyssorhynchus maculipalpis . 
Nyssorhynchus Stephensii. 
Nyssorhynchus Theobaldi. 
Pyretophorus Chaudoyei. 
Pyretophorus costalis. 
Pyretophorus jeypurensis. 
Pyretophorus superpictus. 



70 THE STUDY OF MALARIA 

Not all of these mosquitoes serve equally well as hosts of 
the malarial parasites. Myzomyia Rossii is a very poor car- 
rier of malaria, while the Christophersi is a very efficient car- 
rier. 

As yet very little is known of the relation between the 
species of mosquitoes and species of malarial parasites. Pyre- 
tophorus costalis is known to transmit tertian, quartan, and 
estivo-autumnal malaria, while Myzorhynchus sinensis carries 
tertian and quartan, but not estivo-autumnal malaria. 

It is possible that some mosquitoes acquire a sort of im- 
munity to malaria which may account for their incompetence 
as malaria disseminators. There are certain regions where, 
in spite of members of a malaria-bearing species of mosquito 
and the immigration of infected persons, malaria does not 
spread, though temperature and other conditions are appar- 
ently favorable. 

The food of mosquitoes has much to do with their suscepti- 
bility to infection. Experiments have shown that Anopheles 
maculipennis fed upon fruits and sweets are not readily in- 
fected from feeding upon malarial blood, but if allowed only 
water for several days before and after feeding on malarial 
blood they are almost always infected. 

One feeding upon blood containing parasites does not always 
suffice to infect the mosquito. Daniels, 112 investigating this 
subject, examined fifty-seven mosquitoes which had fed once 
or oftener at intervals of two days. 

Per Cent. 

Nineteen fed only once, and five had zygotes 26.0 

Thirteen fed twice, and six had zygotes 46.0 

Sixteen fed three times, and ten had zygotes 62.0 

Nine fed four times, and six had zygotes 66.6 

Of these 57 anopheles 27, or 47.5 per cent., were infected. 

The effect of fertilization upon the power of mosquitoes to 
transmit malaria is not definitely settled, but it is thought by 
some that fertilized females are the most desirable, if not 
indeed the sole, hosts of the parasite. 

In order that anopheline mosquitoes may be infected from 
malarial blood it is necessary that the sexual forms of the 



ETIOLOGY 71 

parasite be present in sufficient numbers, of proper maturity, 
and suitable proportion of sexes. 

How is the existence of the malarial parasite perpetuated; 
why does not the disease become extinct over winter when 
there are apparently no mosquitoes to further the life history 
of the organism? 

The subject of latent or chronic malaria furnishes the solu- 
tion. The parasites here lie dormant or undergo partheno- 
genesis at longer or shorter intervals, and are ready the fol- 
lowing season for the sexual cycle in the body of the definitive 
host, the mosquito. 

It is possible that in a few instances the parasites persist in 
the bodies of hibernating mosquitoes. While some investiga- 
tions have led to a different conclusion, Martirano has found 
in the neighborhood of Rome as late as the middle of March 
that from 1 to 5 per cent, of anophelines were infected, and 
Stephens and Christophers observed at Freetown, during the 
dry season that from 5 to 20 per cent, were infected. 90 

From analogy with the transference of Texas fever hema- 
tozoa by the tick to its progeny, it has been sought to establish 
such an inheritance of malarial parasites by mosquitoes. While 
Schaudinn found in the ovaries of an anopheline mosquito 
forms which he considered malarial organisms, no other inves- 
tigators have been able to confirm this observation, and it must 
be considered as yet unproven that infected mosquitoes can 
communicate the infection to their offspring. It was also be- 
lieved that infected mosquitoes dying in the water after ovi- 
position and being eaten by larvae might thus communicate 
the parasites to these larvae. This has, however, not been 
determined. 

The relation of the mosquito to malaria explains the preva- 
lence of the latter with reference to season, temperature, and 
rainfall. It explains malaria as a disease chiefly of low alti- 
tudes and marshy regions ; a disease of the country rather than 
of the city. House epidemics of malaria are thus rendered 
clear and the relation of ship malaria and proximity to the 
shore becomes obvious. The bearing of age, sex, and occu- 
pation upon the endemic is in thorough harmony with the 



72 THE STUDY OF MALARIA 

theory. That malaria is more easily contracted at night is 
understood from the feeding habits of the malarial mosquitoes. 
That all measures directed toward the prevention of mosquito 
bites are followed by a commensurate reduction of the preva- 
lence of malaria is one of the strongest arguments. The 
analogy with filiariasis, Texas fever, hematozoan infection of 
birds, and similar diseases strengthens the theory. Numerous 
and accurate experiments have absolutely proven the dissemi- 
nation of malaria by certain mosquitoes. One of the earliest 
of these was that of Dr. Patrick Manson. Mosquitoes fed on 
tertian malarial blood in Rome under the supervision of Bas- 
tianelli were sent in suitable cages to London. There they 
were permitted to bite Dr. Thurburn Manson and Mr. George 
Warren, neither of whom had ever been previously exposed 
to malaria. In due time both developed malaria, and tertian 
parasites were found in the blood at this time and later during 
several relapses. 

The sexual cycle of the parasite within the mosquito has 
been followed many times. 

An objection that has been frequently urged against the 
"mosquito theory" is that there, are numerous localities in 
which mosquitoes abound and from which malaria is entirely 
absent ; indeed, mosquitoes are said to be well nigh intolerable 
in portions of the arctic regions. It must be remembered, 
however, that only a certain subfamily of mosquitoes can 
serve as hosts for the parasite. Furthermore, the surrounding 
temperature must be suitable for the sexual development of 
the parasites within the definitive host. But it cannot be denied 
that there are areas, even in the midst of a malarial country, 
in which anophelines are present, the temperature is favorable, 
and other conditions apparently suitable, but autochthonous 
malaria does not appear. Among such localities reported may 
be mentioned Singapore, Penang, Malacca, Soekaboemie, and 
portions of Brazil, of Italy, and of Lower Egypt. This has 
not as yet been satisfactorily explained, but may be due to an 
acquired immunity on the part of the mosquito, or to the 
influence of their food on the development of the parasite. 

It was formerly maintained that there were highly malarial 



ETIOLOGY 73 

regions in which there were no mosquitoes, and a number of 
such places have been reported. But in each case where 
investigated by a competent observer anopheline mosquitoes 
have been found where malaria is endemic. Koch 69 mentions 
that at Tosari, elevated 1,777 metres, while there was some 
malaria, there were no anopheles. The malaria occurred, 
however, in those who were employed in the neighboring low- 
lands and not in the children who remained in the town. 

The habits of the anopheline mosquitoes are such that they 
may be easily overlooked except by an expert. Retiring to 
dark recesses during the day, biting only at night, and not 
singing a great deal, their presence may not be felt, especially 
by persons in whom the bites do not cause much irritation. 

It may therefore be stated confidently that there is no 
endemic malaria without mosquitoes. 

The misproportion between the number of infected anophe- 
lines and the number of cases of malaria has been cited to 
overthrow the mosquito doctrine. In Algiers Sergent 90 found 
4 per cent, of the anopheles and 100 per cent, of the children 
infected. A. Plehn 79 found in one of the most malarial locali- 
ties, Cameroon, among 860 anopheles only 2.2 per cent, in- 
fected. Stephens and Christophers 11 ^ believe that about 5 per 
cent, of all the anopheles of tropic Africa are infected. At 
Aro they found the sporozoit rate in anopheles caught in native 
huts to be 50 per cent. 

It should be borne in mind that one infected anopheline 
mosquito is capable of infecting a number of persons. Also 
the sporozoit rate varies according to season and according 
to the kind of mosquito, since it has been shown that some 
species are better malaria carriers than others. 

The fact that malaria is decreasing in, or has disappeared 
from, regions formerly highly malarial, but in which malaria- 
bearing mosquitoes are yet found, is another argument which 
has been proposed against the relation of the mosquito to 
malaria. With reference to Great Britain, Nuttall, Cobbett 
and Strangeways-Pigg 114 concluded that: 

1. The disappearance of ague from Great Britain does not 
depend upon the extinction of mosquitoes capable of harboring 
the parasites of malaria. 



74 THE STUDY OF MALARIA 

2. Three species of anopheles (A. maculipennis, A. bifur- 
catus, A. nigripes) are to be found in Great Britain in all 
districts which were formerly malarious, but also in places 
concerning which there is no record of the former prevalence 
of ague. 

3. The anopheles to-day are most numerous in low-lying 
land containing many ditches, ponds, and slowly-flowing water, 
suitable for their habitat, and corresponding to the districts 
where ague was formerly prevalent. 

4. Since the disappearance of ague does not depend upon 
the extinction of anopheles, it is probably due to several causes 
operating together : 

(a) A reduction in the number of these insects consequent 
upon drainage of the land; this being in accord with all the 
older authors, who attributed the disappearance of ague largely 
to this cause. 

(b) Reduction of the population in infected districts as the 
result of emigration about the time when ague disappeared 
from England. This would naturally reduce the number of 
infected individuals and thus lessen the chance of the anopheles 
becoming infected. 

(c) It is possible that the use of quinine has reduced the 
chances of infecting the anopheles through checking the devel- 
opment of the parasites in the blood of subjects affected with 
ague. 

Finally, it has been maintained that persons who have never 
had malaria have contracted it in uninhabited wildernesses, 
where, obviously, only uninfected anophelines would be found, 
since man is the only intermediate host of the parasite. 

To this it may be answered that no such instance has been 
so accurately reported as to prove conclusively that infection 
has ever occurred under these circumstances. 

THE MALARIA-BEARING MOSQUITOES 

The genus Anopheles was established in 18 18 by Johann 
Meigen. The bestowal of the name appears prescient, since 
anopheles signifies troublesome or hurtful. 

Of the fifty or more species and subspecies of anophelines 



ETIOLOGY 75 

now known seven occur in the United States: A. maculipennis, 
A. punctipennis, A. crucians, A. franciscanus, A. barberi, C. 
argyrotarsus, and C. albipes. 

Breeding Places. — The different species of anophelines vary 
a great deal in the choice of a breeding place. Furthermore, 
with each species there may be said to be places of choice and 
places of necessity. 

Contrary to the usual custom of culex, the anopheles usually 
selects water more or less pure in which to deposit her ova. 
Ground water appearing at the surface is especially suitable. 
Pools of at least some degree of permanence are preferred 
to those which might dry before the aquatic stage of the 
insect is completed. Natural accumulations of water more 
often contain anopheles larvae than do artificial collections. 
Pools, ponds, swamps, inlets of lakes, and of small, slowly- 
flowing streams, ditches along roadsides, canals, borrow pits 
along railroads and levees, and rice fields are common breed- 
ing places. Water contained in the tracks of animals may 
harbor larvae. 

When water is scarce, as during the dry season, anopheline 
larvae may be found in tubs, barrels, boats, buckets, bottles, 
cisterns, mollusc and cocoanut shells; in water retained by 
the leaves and stalks of tropic plants, or even within vases in 
dwellings, though these locations are to be regarded as places 
of necessity and not of choice. 

While, as said, clean water is usually chosen by these mos- 
quitoes, at least one species, M. Rossii, is known to breed in 
very foul pools. Another species, M. Listoni, is said to breed 
in swiftly-flowing streams, which is contrary to the usual habit 
of this subfamily. 

In regard to salt water as a medium for anopheline larvae 
many opinions are held. It seems that the species indigenous 
to the United States do not breed in salt water, and this was 
the experience of Celli and other Italian investigators. How- 
ever, Centanni and Orta 115 found anopheles larvae in water 
containing 8.77 per 1,000 of sodium chloride. Ficalbi and 
others 115 found them in water containing 40 to 50 grams of 
sodium chloride per litre. In Algiers and the Dutch Indies 



7 6 



THE STUDY OF MALARIA 



anophelines are found breeding in concentrated sea-water, and 
Banks 116 found M. Ludlowii breeding in sea-water in the Phil- 
ippines. Bancroft in Queensland found a species of anopheles 
breeding in sea-water, and at Accra, on the west coast of 
Africa, Stephens and Christophers 117 obtained numerous an- 
opheline larvse from water containing 6 per cent, of salt. De 
Vogel 68 at Semarang found certain kinds of anopheles breed- 
ing not only in sea-water, but in that which had been con- 
densed to half its volume. 




Fig. 8. — A raft of culex ova. 

Ova of Anophelines. — These mosquitoes do not deposit 
their eggs in a raft-like mass, as do the culex (Fig. 8). They 
are laid in irregular piles, but soon become scattered, lie hori- 
zontally, and may form attractive patterns (Fig. 9) upon the 
surface of the water. In captivity the eggs may be laid upon 
some floating object. 

The ova are from .7 to 1.0 mm. in length by about .16 mm. 
in breadth. They are fusiform in shape and somewhat broader 






Fig. 9. — Patterns assumed by anopheles ova. 



Fig. 10. — Anopheles ova. 



at one end than at the other. The lower surface is convex, 
the upper nearly flat. From the middle third of each side 
protrudes a transversely corrugated membrane which acts as 
a float, somewhat after the manner of the air chambers of 
a lifeboat. These floats are said to be absent only in the ova 
of M. turkhudi. Around the margin of the upper surface of 
the ovum is a frill, usually transversely corrugated. When 
first laid the eggs are whitish, but soon become almost black. 




Fig. ii. — A young anopheles larva. Magnified. 




Fig. 12. — Half-grown anopheles larva. Magnified. 




Fig. 14. — Anopheles pupa. Magnified. 



ETIOLOGY 



77 



The head of the larva lies in the broad end of the egg and 
escapes by loosening a circular cap from this end. It is said 
that if an ovum is partially removed from the water the broad 
end always hangs downward in order that the larva may be 
born into the water instead of into the air. 

The duration of the egg stage varies with the temperature, 
but is generally from two to four days. 

Stephens and Christophers 118 did not succeed in hatching the 
ova after dessication for two or three days, but Grassi 115 is 
said to have hatched them after keeping them dry for twelve 
days. 

The Larva. — The head of the anopheles larva (Fig. 13) is 
more or less globular; the eyes are situated laterally at the 




Fig. 13. — Full-grown anopheles larva. 

broadest part of the head. The antennae are rod-shaped and 
unjointed; at the end are two leaflets, between which arises 
a branched hair. The mouth parts consist of the feeding 
brushes or whorl-organs, the maxillary palps, the mandibles, 
the under lip, and the clypeus. 

The neck is very narrow in the full-grown larva. 

In the young larva (Fig. 11) the thorax is little, if any, 
wider than the head, but in older specimens it is much wider. 

There are nine post-thoracic segments. The first three seg- 
ments bear branched lateral hairs. The third to the seventh 
segments have upon the dorsum a pair of fan-shaped struc- 
tures, known as the palmate hairs (Fig. 17). 

The eighth segment contains the two openings of the respira- 
tory system, which ends abruptly at the dorsum of this seg- 



78 THE STUDY OF MALARIA 

ment without the prolonged breathing tube of the other sub- 
families. 

The ninth or caudal segment bears four flaps containing 
respiratory branchiae. This segment is armed with two large 
tufts of hair. 

The color of the larva varies greatly, according to food and 
environment, and may be grayish, green, almost black, reddish, 
or mottled with black or white. 

The full-grown larva is about 8 mm. in length. 

Anopheline larvae are omnivorous. Their diet consists of 
the spores of algae, diatoms, animalcules, bacilli, other larvae, 
moulted skins, mosquitoes, and other small insects. In cap- 
tivity they eat dry rice greedily. 

The customary location of these larvae is at the surface of 
the water near the edge of the pool, where they may remain 
almost motionless for long periods. The characteristic posi- 




Fig. 17. — A palmate hair. 

tion is parallel with the surface of the water and so close to it 
that a portion of the dorsum appears to rise above the surface, 
which, however, is not the case. When feeding the constant 
motion of the mouth parts creates a flow of water toward the 
mouth, bringing in small particles of food. The head is often 
rotated suddenly, so that it turns through an arc of 180 de- 
grees, the lower surface looking uppermost. On taking hold 
of something too large to swallow the larva will often shake 
the head vigorously and may bend the body to steady the 
particles against the last segments of the body. In captivity 
they often rest with the tail against the sides of the container 
and the head toward the center, when numerous forming a 
fringe around the circumference. Locomotion is very jerky 
and irregular. When disturbed they not infrequently feign 
death. From the behavior of the anopheline larvae it does not 
appear that the sense of sight is very acute. 




Fig. 15. — Head of anopheles. Magnified. 




Fig. 16. — Tail of anopheles larva. Magnified. 




Fig. 20. — Male anopheles. 




Fig. 21. — Female anopheles. 



ETIOLOGY 



79 



Culex larvae have been thawed out of ice in which they 
were imbedded and have proceeded to develop into insects, but 
so far as the writer is aware this has not been done with 
anopheles. The latter have, however, been found in water 




Fig. 1 8. — Adult culex larva. 

under a frozen surface. They may exist for a few hours to a 
few days upon moist mud. 

The duration of the larval stage varies according to tem- 
perature, food, and possibly other conditions. The limits may 
be placed at from ten to twenty-six days. In warm cli- 




Fig. 19. — Resting positions of larvas : a, Culex ; b, anopheles. 



mates when suitable food is abundant the duration is ordinarily 
twelve or fourteen days. In cooler climates and seasons the 
duration is longer. 

Anopheles and culex larvae may be differentiated by the fol- 
lowing gross characteristics : 



8o THE STUDY OF MALARIA 

Anopheles. Culex. 

Habitually at the surface of the At the surface to breathe only. 

water. 

Position parallel with the surface. Hangs at an agle of 50 to 60 de- 
grees to the surface. 

No respiratory tube. Large respiratory tube. 

In full-grown larvae the head is Relatively larger head. 

smaller than the thorax. 

The Pupa. — While the larva bears some resemblance to the 
imago, the pupa resembles neither. It has been compared in 
shape to a hypertrophied comma. The anopheles resembles 
culex more closely in this stage than in any other. The head 
and thorax are enclosed together in a semitransparent shell, 
through which portions of the mouth parts, wings, and legs 
may be detected. Respiration is no longer transacted through 
the eighth abdominal segment, as in the larva, but through the 
trumpet-shaped spiracles or syphons of the thorax (Fig. 2j). 




Fig. 27. — Breathing syphons of (a) anopheles and (b) culex pupae. 

This necessitates a change in position, the abdomen hanging 
and rather curved around the cephalo-thoracic segment. The 
eighth abdominal segment bears a pair of broad paddles for 
locomotion. The young pupa is rather light in color, but 
rapidly becomes darker. 

The pupae are more easily alarmed than the larvae, and when 
disturbed dart wildly downward with rapid jerks. Being of 
lower specific gravity than the water, they rise quickly without 
effort. They do not eat. 

Italian investigators 1,15 observed that the nymphae of some 
mosquitoes resisted freezing and dessication to a remarkable 
degree. Enclosed for several hours in ice, they were yet able 
to develop, and kept in dry soil for two or three days they 
developed when placed in water. 

The duration of the pupal stage is ordinarily from two to 
five days. 




Fig. 22. — Young culex larva. Magnified. 




Fig. 23. — Half-grown culex larva. Magnified. 




Fig. 24. — Culex pupa. Magnified. 




Fig. 25. — Head of culex larva. Magnified. 



// 




Fig. 26. — Tail of culex larva. Magnified. 




Fig. 28. — Male culex. 




Fig. 29. — Female culex. 




Fig. 30. — Young stegomyia larva. Magnified. 





Fig. 31. — Grown stegomyia larva. Magnified. 




Fig. 32. — Stegomyia pupa. Magnified. 




Fig. 33. — Head of stegomyia larva. Magnified. 




Fig. 34. — Tail of stegomyia larva. Magnified. 




'' , *-*.. 



Fig- 35- — Female stegomyia. 



ETIOLOGY 



8l 



The following points may serve to distinguish anopheles 
and culex pupae. 



Anopheles. 

Position in water more horizontal. 

Syphons short, square truncated 
ends, attached to middle of 
thorax. 

Longer anteroposteriorly, nar- 
rower laterally. 



Culex. 

Position more vertical. 

Syphons long and narrow, slit-like 

opening, attached to posterior part 

of thorax. 
Shorter and broader. 



When approaching the emergence of the imago the pupa be- 
comes motionless at the surface of the water ; the abdomen is 
extended parallel with the surface ; minute air bubbles are seen 
under the membrane, which then splits along the dorsal line 
of the thorax. The imago emerges head first, then the thorax 
and wings, then the legs. At this stage the insect is very liable 
to be drowned by a breeze or by a ripple in the water. 





Fig. 36. — Heads of (a) culex and (b) anopheles females. 

The Imago. — The head is subglobular and broader than 
long. The compound eyes occupy most of the front and lateral 
portions of the head. 

The antennae, composed of from fourteen to sixteen joints, 
arise from papillae immediately in front of the eyes, scantily 
haired in females, beautifully plumose in males. 

The proboscis projects from the middle of the anterior 
margin of the head at its lowest plane. The proboscis is highly 
complex. It is composed of a labrum and epipharynx, a hypo- 
pharynx, two mandibles, two maxillae, and a labium which 
forms a sheath for the other parts. The maxillae and mandi- 
bles serve for piercing the skin. The epipharynx conducts the 

6 



&2 



THE STUDY OF MALARIA 



blood or other food to the alimentary canal. Through the 
hypopharynx saliva, containing sporozoits in infected mos- 
quitoes, is injected. 

The palpi or feelers lie to either side and somewhat above 
the proboscis. In anophelines the palpi in both sexes are nearly 
as long as the proboscis, and are clavate in the male. 



FVoboscis"- 
fialpT 

E^2S 

Occ'tput..... 

Protboracic ~- 
lobes 
.MesoHjorax — 

Scahzllum 

Melatborox "** 
First abdominal 
segment" 

Abdomen 




CT< 

Basal " \^ \\ Y^ y^Z, — »=*» 

lobes of --q - \\ «?v </^_^_ 

AAale genitalia v! ^. + 

Basal * - 

r ) i I TVleJafarsu^ 
Gasper — '-j 
froboscis J__ Head of Q 

p^ipi j:::t:^-m ///, 

Antennae \vf --W u YP ec,s \\ 

Basollobesofanrejm?ge_^yY_ fU^ \\fl r frl arsal '' 

Frons- "7 

Vertex / J[ W -r ' 

c I A X \\, .Tarsi 

Dyes — — 

Occiput"—. 

Nope ~ -^.---^ ^ toasts 

Fig. 37.— Diagram of mosquito (after Theobald). 



The thorax is little broader than the head, but is more than 
twice as deep. It is divided somewhat arbitrarily into three 
portions, the prothorax, the mesothorax, and the metathorax, 
though the three segments are fused together into one. From 
each of these segments arises a pair of legs. But little of the 
prothorax is visible from above, a small lobe projecting from 
each shoulder. The mesothorax, comprising the bulk of the 



ETIOLOGY 



83 



thorax, is covered by the scutum. Behind the scutum and the 
origin of the wings is the transverse scutellum, behind which 
is the metathorax or postscutellum. 

The abdomen is larger than the thorax, depressed being 
broader than deep, and is composed of nine segments. The 
upper and under surfaces of each segment are somewhat rigid ; 
laterally the membrane is softer and contains the openings of 
ten respiratory tubes or stigmata. The anus opens ventrally 
upon the eighth segment. The ninth segment bears the exter- 
nal organs of generation. 

The legs, six in number, very long and slender, comprise 
the following joints : The coxa and trochanter, the femur, the 
tibia, and the five-jointed tarsus, the distal joint of which bears 
the claws. 

The wings originate from the posterior portion of the meso- 
thorax. The wing venation is best understood by referring to 



hwiwalcrossvbn 

,-jWa). vein... 



AUXIUAffrYOI 



ffiVDH 3?? VON 

/ 4p/Em / jCTDiriorjr 



SUBWWGtMALCOl 




Fig. 38.- — Diagram of the wing of a mosquito {Culex pipiens), with names of veins, 

cells, etc. (Coquillett). 



the illustration (Fig. 38). The wing scales are of importance 
in classification. 

From the metathorax arises the pair of halteres or balancers, 
club-shaped organs, rudiments of a second pair of wings. Sup- 
plied with one of the largest nerves of the body, they are re- 
garded as sense organs. 

Anopheles is distinguished from culex especially by the palpi, 
which in the former is in both sexes almost as long as the 
proboscis, in the latter the palpi of the female being very short. 
Anopheles is more slender, the head is smaller, and the legs 



84 THE STUDY OF MALARIA 

more delicate. The palpi of the female being thickly scaled 
and lying close to the proboscis give the impression of a thick 
beak, which contrasts strongly with the short palpi and slender 
proboscis of the culex. The wings of the anopheles are 
speckled, which is not the case with any of the common species 
of culex. 

The sitting position of anopheles is characteristic. The 
body of the insect is at an angle with the surface upon which it 
rests, the proboscis pointing toward the surface, sometimes 
even touching it. This angle varies in different anopheline 
species, in some being almost a right angle, when the insect 
appears almost like standing upon its head. The proboscis, 
head, thorax, and abdomen are in the same line. The mosquito 
at rest has been compared to a brad-awl stuck into the wall. 
It often rests upon the first two pairs of legs, waving the last 





a- {? 

Fig. 39. — Resting positions of (a) anopheles and (b) culex. 

pair in the air. Culex at rest is angular and humpbacked. 
Stegomyia may be recognized by its smooth, velvety coat of 
jet black and silvery white, the banded legs and abdomen, and 
the lyre-shaped ornamentation of the thorax. 

The three commonest species of anophelines of the United 
States are thus described by Giles : 119 

Anopheles Maculipennis (Meigen). — "Wings with four 
tufted spots on the wing-field, the costa being uniformly dark 
except at the apex, where its color fades to form a fairly dis- 
tinct spot; tarsi unhanded, but with an apical yellowish spot 
to the first joints. Thorax with four broad ferruginous stripes 
formed of golden hairs, between which the darker ground color 
is left bare, with a tuft of large golden scales on the anterior 
border. Abdominal segments brown with yellowish basal 
markings ; anterior femora not thickened at the base. 



ETIOLOGY 85 

"Female. — Head with two patches of creamy scales divided 
by a central line, the rest of the head with black scales, a small 
tuft of white hairs in front; borders of the eyes white; eyes 
deep purplish-black ; antennae dark brown with pale bands and 
with ferruginous basal joint, pale pubescence, and brown hairs ; 
proboscis brown ; palpi yellowish-brown with dense, dark scales 
at the base, which is swollen, shorter than the proboscis. Leg's 
with pale coxae ; femora and tibiae yellowish-brown below, cov- 
ered with dark-brown scales above; knee spot yellow, apex of 
the tibiae paler; tarsi slightly darker than the rest of the leg. 

"Male. — Antennae banded, plume hairs brown, last joint 
darker ; proboscis black to dark brown ; palpi dark brown ; the 
last two joints, which are clubbed, have a number of short 
golden hairs internally and are yellow in color, clothed with 
thick black scales, through which the yellow underground 
shows; the last joint is truncated. Length 4 to 7.5 mm. male, 
to 8 or 10 mm. female. This species varies greatly in size, the 
wings shown me in Italy by Professor Grassi being quite small, 
while some Canadian specimens in the British Museum are 
huge gnats, and to illustrate this I have superposed on the 
plate the drawing of one of Grassi's specimens on the outline 
of a Canadian specimen." 

Anopheles Punctipennis (Say.). — "Wings with the costa 
black, interrupted by a single large ferruginous spot a little 
outside the transverse veins, and involving the first and second 
longitudinal veins. There is also a small apical spot, and some 
yellow spots near the tips of the long veins, but otherwise the 
wing is very dark and has no interruptions of the fringe. Legs 
and tarsi uniformly nearly black. Thorax and abdomen deep 
brown, nude but for some yellowish-brown hairs. Wings 
much longer than abdomen. 

"Head black with scanty whitish frontal tuft. Palpi and 
proboscis dark yellowish-brown, unhanded but rather lighter at 
the tips. Halteres brown. This is not likely to be confused 
with any other species than my An. gigas, but may be distin- 
guished by the base of the wing internal to the large spot being 
uniformly black instead of spotted with yellow, as in gigas, as 
well as its being altogether a darker species. There appears 



86 THE STUDY OF MALARIA 

to be a triangular swelling at the base of the abdominal seg- 
ments. It may be distinguished from An. crucians by the costa 
of the latter being uniformly dark and by its having two instead 
of three dark spots on the sixth longitudinal vein. The middle 
spot extends much further across the wing than in the Sinensis 
group, and the tarsi are unhanded. Length 5 to 7 mm." 

Anopheles Crucians (Wied.). — "Wings with white spots 
here and there on the brown veins, uniform along the costa; 
tarsi unbanded, dusky brown; abdomen uniformly brown with 
grey hairs. Thorax red-brown with linear markings. 

"Description from Wied., A. Z. I., p. 12 : 'Tawny; the thorax 
with three deeper-tinted lines ; the abdomen covered with grey 
hairs; the wings with dusky spots and costa. Length 2^/2. lines 
(German).' 

"Coquillett, in his recent synoptic table of North American 
Culicidce, states that 'the scales of the last veins are white, 
marked with three black spots ; palpi marked with white at the 
bases of the last four joints,' and without any spot on the 
costa, as seen in A. punctipennis. 

"Professor Nuttall sent Mr. Theobald two females from 
America in spirit, which, although much damaged, show the 
two features mentioned by Coquillett very clearly, readily dis- 
tinguishing the species from the C. punctipennis of Say." 

The following key to the mosquitoes of North and Middle 
America is that of Mr. Coquillett, 120 of the Department of 
Agriculture, by whose kind permission it is here reproduced : 



A CLASSIFICATION OF THE MOSQUITOES OF NORTH AND MIDDLE 

AMERICA 

Table of the Subfamilies 

A. Scutellum convex behind, never distinctly three-lobed; posterior end of 

the thorax bare ; small cross-vein 
usually situated considerably before 
the root of the third vein and con- 
nected with it by a stump of a vein; 
claws of the female simple. 
B. Proboscis straight or almost so ; back of the head devoid of 

broad appressed scales, but with many 
narrow outstanding ones ; body never 
with metalescent scales ; first sub- 
marginal cell longer than its petiole ; 
claws simple in both sexes. 



ETIOLOGY 87 

1. Anophelin^e 

BB. Proboscis strongly decurved ; back of the head wholly covered 

with broad appressed scales, but de- 
void of narrow, outstanding ones; 
body covered with broad appressed 
metalscent scales ; first submarginal 
cell less than half as long as its 
petiole; some of the claws of the 
male toothed. 

2. Megarhinin^e 

AA. Scutellum distinctly three-lobed ; small cross-vein usually situated 

beyond the root of the third vein. 
C. Posterior end of the thorax bare. 

D. First submarginal cell at least nearly as long as its 
petiole; some of the claws of the 
male toothed ; thorax never with 
metallic bluish scales arranged in 
lines or spots. 
E. Second joint of the antennae less than eight 
times as long as wide in both sexes, 
with many long hairs, longer and 
more numerous in the male. 
F. Femora bearing many outstanding scales; 
wing scales narrow. 

3. PSOROPHORIN^E 

FF. Femora devoid of outstanding scales. 1 

4. Culicin^e 

EE. Second joint of the antennae unusually long, in 
both sexes over fourteen times as 
long as wide ; antennae in both sexes 
with a few short hairs only. 

5. Deinoceritin^e 

DD. First submarginal cell less than half as long as its 
petiole ; claws simple in both sexes ; 
thorax with metallic bluish scales 
which form lines or spots. 

6. Uranotveniin.^: 

CC. Posterior end of the thorax behind the scutellum bearing 

several bristles and sometimes with 
a few scales ; claws simple in both 
sexes ; antennae similar in the two 
sexes, bearing many long hairs. 

7. Trichoprosoponin/e 

1. Subfamily ANOPHELINjE Theobald 
Table of the Genera 

1. Abdomen with clusters of broad, outstanding scales along the sides ; 

outstanding scales on the veins of the wings chiefly rather broad. . . 4 
Abdomen never with such clusters of scales 2 

2. Outstanding scales on the veins of the wings lanceolate, or broader, 

strongly tapering to their bases 3 

Outstanding scales very narrow, linear, very slightly, if at all, tapering 
to their bases ; feet with white bands. (Middle America) . .Mysomyia 

3. Veins of the wings having the outstanding scales rather narrow, lanceo- 

late ; feet wholly black Anopheles 

Veins of the wings with many broad, obovate, outstanding scales ; feet 
with narrow, indistinct white bands at the bases of some of the 
joints. (Middle America) Cycloleppteron 



Except in the genus Aedeomyia, which has broad wing scales. 



88 THE STUDY OF MALARIA 

4. Upper side of thorax and scutellum bearing many appressed lanceolate 
scales ; outstanding scales on the veins of the wings rather narrow, 

lanceolate. (Florida and southward) Cellia 

Upper side of thorax and scutellum with hairs only; many rather broad, 
obovate outstanding scales on the veins of the wings. (Middle 
America) Nototricha n. gen. 

Genus MYZOMYIA Blanchard 

(Synonym: Grassia Theobald) 

Wings black-scaled and with several white-scaled patches ; feet black, 
banded with white; thorax gray and with four black stripes. (West 
Indies) lutsii Theob. 

Genus ANOPHELES Meigen 
(a) Table of the Species 

1. Wings marked with spots of dark or light-colored scales 2 

Wings unspotted; length of the head and body about 3 mm. 

barberi Coq. 

2. Front margin of the wings with a patch of whitish scales at a point 

about three-fourths of the way from base to apex of the wing. ... 5 

Front margin of the wings wholly black-scaled 3 

3. Sixth, or last, vein of the wings wholly black-scaled 4 

Sixth vein white-scaled and with three patches of black scales. 

crucians Wied. 

4. Hind tibiae yellowish-white-scaled on the apical fourth; first vein of 

the wings with a patch of yellow scales before its middle and another 

on the apex. (Central America) eiseni Coq. 

Hind tibiae narrowly yellowish-white scaled at the extreme apex only, 
first and other veins with black scales only maculip ennis Meig. 

5. Scales of the last vein of the wings white, those at its apex black ; 

third vein white-scaled and with two patches of black scales 6 

Scales of the last vein white, those at each end black; third vein black- 
scaled, the extreme apex white-scaled punctipennis Say. 

6. Fourth vein of the wings black-scaled, the apices of the forks and 

usually also a patch at the cross veins white-scaled. 

franciscanus McC 

Fourth vein white-scaled, the forks (except their apices) and on either 

side of the cross veins black-scaled pseudo punctipennis Theob. 

(b) List of the Species and Synonyms 

barberi Coq. maculipennis Meig. 

crucians Wied. annulimanus van der Wulp. 1 

eiseni Coq. bifurcatus Meigen (1804; not of 

franciscanus McCracken. Linne, 1758). 

quadrimaculatus Say. 
pseudopunctipennis Theob. 
punctipennis Say. 
hyemalis Fitch. 

(c) Unrecognized Species 

bifurcatus Linne, nigripes Staeger, and walkeri Theobald. These species 
are said to have unspotted wings, like barberi, but are larger, have yellow 
scales on the thorax, etc. 

pictus Loew. This species, described from Asia Minor, was also re- 
corded from North America by its author, but he evidently mistook some 

''At my request Dr. C. Ritsema Cz compared specimens of maculipennis 
with the type of annulimanus in the Leyden Museum, and informed me 
that they are identical. 



ETIOLOGY 89 

other species for it. No specimen of his species has been reported from 
this country since the time he published the statement. 

quinquefasciatus Say (ferruginosus Wied.). This is a synonym of 
Culex pipiens L. 

Genus CYCLOLEPPTERON Theobald 

Thorax with a velvety black dot near the middle of either side ; feet 
almost unicolorous, not distinctly banded; wing scales chiefly brown 
or black, a patch of yellow ones at a point about two-thirds the 
length of the front margin and four smaller ones at the apex of 

the wing grabhami Theob. 

(C. medio punctatus Theob. belongs to the following genus.) 

Genus NOTOTRICHA, New Genus 

Thorax with a velvety black dot near the middle of either side and a 
larger spot in front of and extending upon the scutellum; legs 
brown-scaled and with many dots and narrow bands of light-colored 
scales mediopunctata Theob. 

Genus CELLIA Theobald 

(Synonym: Arribalzagia Theobald) 

(a) Table of the Species 

1. Hind feet from the middle of the second joint largely or wholly 

snow-white 2 

Hind feet black, mottled with whitish and with bands of the same 
color at the sutures of the joints maculipes Theob. 

2. With a black band at the base of the last joint of each hind foot. 

albimanus Wied. 
Without such a band argyritarsis Desv. 

(&) List of the Species and Synonyms 

albimanus Wied. argyritarsis Desv. 

albipes Theob. albitarsis Arrib. 

cuber sis Agramonte. maculipes Theob. 
tarsimaculatus Goeldi. 

2. Subfamily MEGARHININ/E Theobald 
(Synonym: Lynchiellina Lahille) 

Genus MEGARHNINUS Desvoidy 
(Synonym: Lynchiella Lahille) 

(a) Table of the Species 

1. Feet with a white band, at least on the hind ones; middle joint of the 

male palpi with many yellow scales on the outer side ; hairs of the 

male antennse long and dense 2 

Feet wholly black on at least their upperside ; palpi wholly purple-scaled ; 
hairs of the male antennae rather short and sparse. (West Indies.) 

violaceus Wied. 

2. Middle and front feet wholly black portoricensis Roeder 

Middle and usually the front feet with a white band on each. 

rutilus Coq. 

(&) List of the Species and Synonyms 

portoricensis Roeder. violaceus Wied. 

ferox Walker (not of Wiedemann). purpureus Theob. 
rutilus Coq. 



90 THE STUDY OF MALARIA 

(c) Unrecognized Species 

grandiosus Will., hamorrhoidalis Fab., and longipes Theob. These three 
species have been reported from Mexico. 

3. Subfamily PSOROPHORIN^ Mitchell 

Genus PSOROPHORA Desvoidy 

(Synonym: Chrysoconops Goeldi) 

(a) Table of the Species 

1. Abdomen yellow or brownish, its scales yellowish 3 

Abdomen black, its scales chiefly purple ; upper side of the thorax 

polished black, usually white-scaled toward the sides 2 

2. Front and middle femora black, their scales purple except at the narrow 

apex of each femur, where they are white. (Middle America.) 

cilipes Fab. 
Front and other femora yellow, yellow-scaled, their broad apices black- 
scaled howardii Coq. 

3. Veins in the front half of the wings, except toward their apices, deep 

yellow, their scales of the same color, scales on the front half of the 

thorax golden yellow. (West Indies) fulva Wied. 

Veins and scales of the wings wholly brown, scales in the middle of the 
upper side of the thorax golden yellow, those toward the sides white. 

ciliata Fab. 

(b) List of the Species and Synonyms 

ciliata Fab. fulva Wied. 

conterrens Walk. flavicosta Walk. 

molestus Wied. ochripes Macq. 

pert err ens Walk. howardii Coq. 

rubidus Desv. 
cilipes Fab. 

(c) Unrecognized Species 
scintillans Walk. This species has been recorded from the West Indies. 

4. Subfamily CULICIN^ Theobald 

(Synonyms: Aedeomyince Theobald, Hcemagogincz Lutz) 

Table of the Genera 

1. Claws of the female toothed on at least the front and middle feet; 

some of the claws of the male also toothed 4 

Claws of the female simple 2 

2. Palpi of the male at least three-fourths as long as the proboscis. ... 10 
Palpi of the male at most only one-half as long as the proboscis. (Mid- 
dle America) 3 

3. Head posteriorly with very narrow scales and with a patch of broad 

ones on each side 18 

Head sparsely or densely covered with broad scales posteriorly 21 

4. Scales along the sides of the upper surface of the thorax narrow, 

almost linear, legs never with outstanding scales 6 

Scales along the sides of the upper surface of the thorax chiefly rather 
broad, obovate, hind part of the head with many similar scales scat- 
tered about 5 

5. Legs devoid of outstanding scales Lepidosia 

Legs bearing many outstanding scales, at least on the hind feet, all feet 

black, the hind ones alone partly white Janthinosoma 



ETIOLOGY 



91 



6. Back part of the head densely covered with broad, appressed scales 

except sometimes a narrow stripe in the middle 7 

Back part of the head sparsely covered with narrow, almost linear 
scales and with a patch of broad ones on each side 8 

7. Clypeus bearing several scales or hairs, scutellum with broad scales 

only Stegomyia 

Clypeus bare, scutellum with narrow scales only. (Middle America.) 

Verrallina 

8. Wing veins having the outstanding scales narrow, lanceolate, only 

slightly tapering to the base 9 

Wing veins having many very broad outstanding scales which taper 
strongly to their bases ; several of the scales are hollowed out at 
their apices Lepidoplatys 

9. Palpi of the male less than one-fourth as long as the proboscis. .Aedes 
Palpi of the male about as long as the proboscis Ochlerotatus 

10. Head densely covered behind with broad, appressed scales, except a 

narrow stripe in the middle, or else the thorax has six lines of 

silvery scales 23 

Head bearing narrow, almost linear appressed scales behind and with 
a patch of broad ones on each side; thorax never with lines of 
silvery scales 11 

11. Outstanding scales on the veins behind the first one narrow and of 

nearly a uniform width 12 

Outstanding scales on at least the apical half of the wings broad, con- 
siderably narrowed at their bases 17 

12. Feet white at each end of some of the joints or else wholly black, 

in which case the abdomen is wholly black-scaled, or else it has cross- 
bands of light-colored scales 13 

Feet white at the bases only of some of the joints, or else wholly 
black, in which case the abdomen is black-scaled and with the front 
corners of some of the segments white-scaled Grabhamia 

13. Costa of the wings not spotted 14 

Costa black-scaled and with three large spots of pale yellow scales. 

(Middle America) , Lutzia 

14. Thorax with two distinct bare stripes near the middle of the upper 

side ; hind cross-vein at least its own length from the small cross 

vein Culicella 

Thorax without bare stripes 15 

15. Scales of the wings collected into spots ; hind cross-vein much less 

than its length from the small cross-vein Theobaldia 

Scales of the wings uniformly distributed 16 

16. Hind cross-vein much less than its own length from the small cross- 

vein Culiseta 

Hind cross-vein situated at least nearly its own length from the small 
cross-vein Culex 

17. Basal half of the wings having the outstanding scales of the veins nar- 

row and almost linear; proboscis wholly black Melanoc onion 

Basal half of the wings having many broad, outstanding scales on the 
veins 20 

18. Wing veins having the outstanding scales narrow, almost linear. ... 19 
Wing veins having the outstanding scales rather broad, oblanceolate ; 

palpi of the male almost one-half, those of the female less than one- 
fifth, as long as the proboscis Tinolestes 

19. Palpi in both sexes about one-third as long as the proboscis. .Micraedes 
Palpi in both sexes less than one-fifth as long as the proboscis. 

Isostomyia n. gen. 

20. The outstanding scales on the veins of the wings only moderately 

broad, over twice as long as broad, their apices rounded; proboscis 

and feet usually with light-colored bands Coquillettidia 

The outstanding scales chiefly unusually broad, their apices flat or 
hollowed out Tceniorhynchus 



92 THE STUDY OF MALARIA 

21. Outstanding scales on the wing veins unusually broad; femora toward 

their apices bearing several elongate, outstanding scales ; body devoid 

of blue scales Aedeomyia 

Outstanding scales on the wing veins narrow, almost linear, legs devoid 
of outstanding scales, head and body chiefly blue scaled 22 

22. Base of the first submarginal cell nearer to the base of the wing than 

is that of the second posterior cell ; palpi of the male less than one- 
fifth as long as the proboscis, the abdomen bearing only a few hairs 

on the under side of the penultimate segment Hcemagogus 

Base of the first submarginal cell noticeably nearer to the apex of the 
wing than is the base of the second posterior cell; palpi of the 
male about one-half as long as the proboscis ; abdomen of the male 
with a large cluster of outstanding, blunt spines on the under side 
of the penultimate segment Cacomyia n. gen. 

23. Scutellum bearing both broad and narrow scales ; head behind covered 

with broad appressed scales except a median stripe of rather narrow 
ones; outstanding scales on the wing veins narrow. (Middle 

America) Gymnometopa 

Scutellum with narrow scales only 24 

24. Back of the head covered with broad appressed scales except a median 

stripe of rather narrow ones ; outstanding scales on the wing veins 

narrow. (Middle America) Howardina 

Back of the head with narrow scales only; many rather broad, out- 
standing scales on the wing veins Pneumaculex 

Genus LEPIDOSIA Coquillett 

Our two species have the scales of the abdomen deep blue, except those 
of the first segment and a broad, usually interrupted band on the 
apices of the other segments, which are pale yellow or whitish. 

Hind feet wholly black cyanescens Coq. 

Hind feet black, the last joint white mexicana Bell. 

Genus JANTHINOSOMA Arribalzaga 

(Synonym: Conchyliastes Theobald) 

(a) Table or the Species 

1. Last two joints of the feet wholly white 3 

Last joint largely or wholly black, the preceding joint chiefly white.. 2 

2. Scales on the upper side of the thorax yellow varipes Coq. 

Scales brown, those toward the sides yellow discrucians Walk. 

3. Upper side of the thorax yellow-scaled and with a broad stripe of 

brown scales in the middle lutsii Theob. 

Upper side of the thorax wholly yellow-scaled posticata Wied. 

(b) List of the Species and Synonyms. 

discrucians Walker (not of Giles posticata Wiedemann (not of Theo- 

and Theobald). 1 bald). 

arribalzaga Giles. musica Say. 

lutzii Theob. varipes Coq. 

albitarsis Neveu-Lemaire (not of johnstonii Grabham. 

Theobald). 

discrucians Giles and Theobald 
(not of Walker). 

1 The form referred to this species by these two authors has the entire 
apex of the hind feet wholly white, whereas in his original description 
Walker expressly states, both in the Latin diagnosis and in the English 
description, that there is only a subapical white band in discrucians, the 
remainder of the feet being purple. 



ETIOLOGY 93 

(c) Unrecognized Species 

terminalis Coquillett (posticata Theobald, not of Wiedemann), was 
described from St. Lucia, W. Ind., and differs from all of the other 
species in that the last joint only of the hind feet is white. 

Genus STEGOMYIA Theobald 

(a) Table of the Species 

Thorax marked with a pair of curved silvery stripes forming a figure 
which somewhat resembles a lyre; proboscis unicolorous black, feet 
black and with white bands at the bases of some of the joints. 

calopus Meig. 

(b) List of the Species and Synonyms 

calopus Meig. calopus Meig — Continued. 
annulitarsis Macq. kononpi Brulle. 

bancroftii Skuse. luciensis Theob. 

elegans Ficalbi. mosquito Desv. 

exagitans Walk. queenslandensis Theob. 

excitans Walk. rossii Giles. 

fasciata Fab. tceniatus Wied. 

formosa Walk toxorhynchus Macq. 

frater Desv. viridifrons Walk. 

impatibilis Walk. zonatipes Walk. 

inexorabilis Walk. 
(S. sexlineata Theob. belongs to the genus Gymnometopa.) 

Genus VERRALLINA Theobald 

Upper side of the thorax black-scaled, the sides in front of the wings 

white-scaled insolita Coq. 

Upper side of the thorax wholly whitish-scaled laternaria Coq. 

Genus LEPIDOPLATYS Coquillett 

(a) Table of the Species 

Scales of the wings mixed brown and white; feet with broad white bands 
at the bases of some of the joints, tibiae not distinctly banded. 

squamiger Coq. 

(b) List of the Species and Synonyms 

squamiger Coq. 
deniedmannii Ludlow. 

Genus AEDES Wiedemann 1 

Upper side of the thorax golden-yellow scaled ; abdomen black-scaled and 
with a band of yellow scales at the bases of the segments ; feet 

unicolorous black fuscus O. S. 

{A. smithii belongs to Wyeomyia.) 

Genus OCHLEROTATUS Arribalzaga 

(Synonyms: Culicada Felt, Culicelsa Felt, Ecculex Felt, Protoculex 
Felt, Pseudoculex Dyar.) 

'This genus has commonly been credited to Meigen, but he expressly 
states that he had not seen a specimen and that both the name and de- 
scription had been furnished to him by Wiedemann. 



94 THE STUDY OF MALARIA 

(a) Table of the Species 

1. Ground color of the thorax bright yellow; the scales and bristles of 

the head and thorax wholly yellow 2 

Ground color of the thorax brown or black 3 

2. With an ovate black spot above the insertion of each wing; feet not 

distinctly two-colored, claws of the hind ones simple. 

bimaculatus Coq. 

Without such a spot ; feet dark colored and with white bands at the 

bases of some of the joints. (Middle America) knabi Coq. 

3. Feet dark colored and with white bands 19 

Feet not distinctly banded, proboscis unhanded 4 

4. Scales of the abdomen black, sometimes a crossband or pair of spots 

of light-colored scales on some or all of the segments 5 

Scales of the abdomen yellow, except a pair of spots of black ones 
on some of the segments; claws toothed on all of the feet in the 
female spenceri Theob. 

5. Light-colored scales of the abdomen forming crossbands situated at 

the bases of the segments 6 

Light-colored scales, when present, forming spots on the sides of some 
of the segments 14 

6. Upper side of the thorax yellow-scaled and with three stripes of brown 

scales ; scales of the wings wholly brown ; all the claws of the female 

toothed trivittatus Coq. 

Upper side of the thorax not marked like this 7 

7. Thorax with a brown-scaled stripe along the sides and with a wider 

space of white scales in the middle; scales of the wings wholly 

brown; all of the claws toothed in the female dupreel Coq. 

Thorax not marked in this manner 8 

8. Sides broadly and the front end of the thorax whitish-scaled ; back 

part of the head also whitish-scaled; all claws toothed in the 

female 9 

Sides and front end of the thorax yellow or brown scaled 10 

9. Middle of the thorax with a broad stripe of brown scales. 

pretans Grossb. 
Middle of the thorax having the scales yellow and whitish. 

cinereoborealis Felt. 

10. The scales in the middle of the thorax as dark as, or darker than, 

those along the side 11 

The scales in the middle of the thorax yellow, those along the broad 
sides brown; claws of the hind feet simple in the female. 

bracteatus Coq. 

11. Bristles of the scutellum yellow 12 

Bristles of the scutellum chiefly black ; upper side of the thorax golden- 
yellow-scaled and devoid of stripes of darker scales, although two 
darker stripes sometimes appear where the scales are very sparse, 
each stripe being scarcely one-half as wide as the yellow-scaled space 
between it and the other stripe pullatus Coq. 

12. In the middle of the thorax the scales are wholly yellow 13 

In the middle of the thorax is a pair of brown-scaled stripes, each 

stripe being slightly wider than the yellow-scaled space between it 
and the other stripe lasarensis F. & Y. 

13. Claspers of the male with a long, stout spine near the base of the 

inner side impiger Walk. 

Claspers without such a spine abserratus Felt. 

14. With a median stripe of scales on the thorax of a different color from 

those along the sides 15 

Without such a stripe ; abdomen black-scaled and with the front angles 
of some of the segments white-scaled; claws on all of the feet of 
female toothed. (Middle America) nubilus Theob. 



ETIOLOGY 95 

15. Scales in the middle of the thorax, at least on its anterior half, white, 

the remainder brown; claws on all of the feet of the female 

toothed 16 

Scales in the middle of the thorax black, the remainder yellow or 
whitish 18 

16. Stripe of white scales in the middle of the thorax extending entirely 

across the latter 17 

Stripe of white scales confined to the anterior two-thirds of the 
thorax confirmatus Arrib. 

17. White-scaled stripe of the thorax much narrower than the brown- 

scaled portion on each side of it serratus Theob. 

White-scaled stripe wider than the brown-scaled portion on each 
side of it dupreei Coq. 

18. Upper surface of the thorax white-scaled toward the sides ; claws on 

the hind feet of the female simple triseriatus Say. 

Upper surface of the thorax golden-yellow-scaled toward the sides ; 
claws on the hind feet of the female toothed aurifer Coq. 

19. Proboscis blackish and with a white band near the middle ; white 

bands of the feet confined to the bases of the joints, except on the 

hind feet, the last joint of which is sometimes wholly white 20 

Proboscis blackish, not distinctly banded near the middle 22 

20. Abdomen black-scaled, each segment with a basal band and median 

longitudinal stripe of yellowish scales, and with a white-scaled spot 

in the middle of each side 21 

Abdomen black-scaled, each segment with a band at the base and a 
spot in the middle of each side white-scaled, wing scales wholly 
black tceniorhynchus Wied. 

21. Wing scales mixed black and yellowish; light colored scales of the 

legs yellow, usually a whitish band in the middle of the first joint 

of the feet solicitans Walk. 

Wing scales wholly black ; light colored scales of the legs pure white, 
first joint of the feet never with a light colored band in the middle. 

mitchellcB Dyar. 

22. Joints of the feet having the white bands situated at both ends of 

some of them, last joint of the hind feet white 23 

Joints of the feet having the white bands situated at the bases only 
of some of them, last joint of the hind feet black except sometimes 

its extreme base 28 

2.2,. Black scales mixed with white ones on the wings ; abdomen whitish 
or yellow-scaled and with a pair of black-scaled spots on some of 

the segments 24 

Black scales only on the wings, abdomen black-scaled, sometimes with 
a band of white scales at the bases of the segments 25 

24. Stripe of scales in the middle of the thorax deep golden brown, cover- 

ing more than one-fifth of the width of the thorax, its borders 

well defined. (Salt water species) latimttatus Coq. 

Stripe pale brown, covering less than one-ninth of the width of the 
thorax, its borders not strongly marked, usually a narrow stripe of 
brown scales on each side of it separated by yellowish white scales. 
(Fresh water species) curriei Coq. 

25. Upper side of the thorax light-yellow-scaled and with a broad stripe 

of black scales in the middle; palpi wholly black-scaled in both sexes; 
abdomen black-scaled and with a band of white scales at the base of 

each segment atro palpus Coq. 

Upper side of the thorax not marked as above; palpi with whitish 
scales at the apices in the female and with bands of them in the 
male 26 

26. Segments of the abdomen with distinct whitish bands at their bases ; 

scales of the upper side of the thorax brown and light yellowish. 

varipalpus Coq. 

Segments of the abdomen never with distinct whitish bands; scales of 

the upper side of the thorax wholly yellow 27 



9 6 



THE STUDY OF MALARIA 



27. Hind feet almost wholly white-scaled nivitarsis Coq. 

Hind feet largely black-scaled canadensis Theob. 

28. Dorsum of the abdomen black-scaled and with a band of light-colored 

scales at the base of each segment 30 

Dorsum of the abdomen not marked as above 29 

29. Abdomen wholly light-yellow-scaled fletcheri Coq. 

Abdomen black-scaled and with white spots on the sides ; thorax black- 
scaled and with four lines of yellow scales. (Middle America.) 

quadrivittatus Coq. 

30. White band at the base of the second joint of the hind feet covering 

at least one-third of the length of the joint; claws of the hind feet 

toothed in the female 32 

White band covering less than one-fourth of the length of the second 
joint of the hind feet 31 

31. Seventh segment of the abdomen almost wholly yellow-scaled, many 

yellow scales in the central portion of the preceding segment; claws 

of the hind feet of the female simple cantator Coq. 

Seventh and preceding segment chiefly black-scaled; claws of the hind 
feet of the female toothed sylvestris Theob. 

32. Claspers of the male having, near the base of the inner side, a large 

process thickly covered with hairs fitchii Felt. 

Claspers without such a process. 

subcantans Felt, abfitchii Felt, vittata Theob. 

(b) List of the Species and Synonyms 



abfitchii Felt. 

siphonalis Grossb. 
abserratus F. & Y. 
atropalpus Coq. 
aurifer Coq. 
bimaculatus Coq. 
bracteatus Coq. 
cantator Coq. 
canadensis Theob. 
cinereoborealis F. & Y. : 

iridiums Dyar. 
confirmatus Arrib. 
curriei Coq. 
dupreei Coq. 
fitchii F. & Y. 
fletcheri Coq. 
impiger Walk. 

implacabilis Walk, 
knabi Coq. 
lativittatus Coq. 
lazarensis F. & Y. 



mitchellae Dyar. 
nivitarsis Coq. 
nubilus Theob. 
pretans Grossb. 
pullatus Coq. 
quadrivittatus Coq. 
serratus Theob. 

mathisi Neveu-Lem. 
sollicitans Walk, 
spenceri Theob. 

idahoensis Theob. 
subcantans Felt, 
sylvestris Theob. 
taeniorhynchus Wied. 

damnosus Say. 
triseriatus Say. 

nigra Ludlow (Finlaya). 
trivittatus Coq. 
varipalpus Coq. 

sierrensis Ludlow. 



(c) Unrecognized Species 

aestivalis Dyar, auroidcs Felt, excrucians Walker, hirsuteron Theob., 
inconspicuus Grossb., nemorosus Meigen, onondagensis Felt, pallidohirta 
Grossb., portoricensis Ludlow, provocans Walker, punctor Kirby, reptans 
Meigen, stimulans Walker, testaceus van der Wulp, and tortilis Theobald. 

J The writer's copy of Science containing the original description of this 
species was received September 2, 1904, and the National Museum copy 
is stamped as having been received on the same date. The writer's copy 
of the Journal of the New York Entomological Society which contains 
the original description of trichurus was received September 6, 1904; the 
National Museum copy and that of the U. S. Department of Agriculture 
are stamped with the same date — September 6, 1904. 



ETIOLOGY 97 

Genus GRABHAMIA Theobald 

(Synonym: Feltidia Dyar) 

(a) Table of the Species 

i. Feet unicolorous brown, wing scales wholly brown. (West Indies) . . 2 

Feet brown and with bands of white scales at bases of some of the 

joints 3 

2. With an ovate, velvety-black spot above the insertion of each wing; 

abdomen black-scaled, unmarked ocellatus Theob. 

Without such a spot ; abdomen black-scaled and with a white-scaled 
spot in the front angles of the posterior segments. 

scholasticus Theob. 

3. Proboscis black-scaled and with a light-colored band near the middle ; 

a white band before the apex of each hind femur 4 

Proboscis wholly black ; abdomen black-scaled and with a white band 
at the bases of the segments; no white band before the apex of the 
hind femora. (West Indies) imitator Theob. 

4. Wing scales black and whitish 5 

Wing scales wholly black ; abdomen black-scaled and with a narrow 

white, usually interrupted, band at apex of each segment. (West 
Indies) confinis Arrib. 

5. Last vein with many black scales on the basal portion 6 

Last vein wholly white-scaled on the basal two-thirds ; light and dark 

scales of the wings collected into spots, costa mixed black and whitish 
scaled and with a long whitish spot beyond the apex of the auxiliary 
vein discolor Coq. 

6. Costa and veins bearing mixed black and whitish scales, the latter not 

forming distinct spots 7 

Costa black and whitish scaled, the apical half with four long spots of 
whitish scales alternating with three long spots of black ones. 

signipennis Coq. 

7. First joint of the hind feet light colored in the middle, a small but 

distinct black-scaled spot at the base of the third vein. 

jamaicensis Theob. 

First joint of the hind feet black in the middle, no distinct black spot at 

the base of the third vein pygmceus Theob. 

(b) List of the Species and Synonyms 

confinis Arrib. ocellatus Theob. 

discolor Coq. pygmaeus Theob. 

imitator Theob. antique Giles, 

jamaicensis Theob. nanus Coq. 
confinis auct. (all references to scholasticus Theob. 

its occurrence in the United signipennis Coq. 

States). 

(G. deniedmannii Ludlow belongs to Lepidoplatys.) 

Genus LUTZIA Theobald 

Joints of the feet white at each end, abdomen black-scaled and with a 
large apical spot of white scales on each segment bigotii Bell. 

Genus CULICELLA Felt 

(a) Table of the Species 

Feet narrowly white at the bases of some of the joints, proboscis without 
a lighter band near the middle, abdomen black-scaled and with a 
broad band of yellow scales at the base of each segment. . .dyari Coq. 
7 



98 THE STUDY OF MALARIA 

(&) List of the Species and Synonymy 
dyari Coq. 
brittoni Felt. 

Genus THEOBALDIA Neveu-Lemaire 
(a) Table of the Species 

Front side of the hind tibiae chiefly black-scaled, the apices very broadly 
whitish-scaled, white bands of the feet narrow, the dark spots on 
the wings large incidens Thorn. 

Front side of the hind tibiae with many yellow scales, the apices narrowly 
and indistinctly whitish-scaled ; the dark spots on the wings small. 

annulata Schrank. 



(b) List of the Species and Synonyms 

lk. 

is. 
variegata Schrank. 



annulata Schrank. incidens Thom. 

affinis Stephens. particeps Adams. 



Genus CULISETA Felt 
(a) Table of the Species 

Wing scales wholly brown, abdomen brown-scaled and with bands of light- 
colored scales at the bases of the segments in both sexes. 

absobrinus Felt. 

Wing scales mixed brown and yellowish in the female, abdomen brown- 
scaled and with bands of light-colored scales in the female, un- 
handed in the male consobrinus Desv. 

(&) List of the Species and Synonyms 

absobrinus Felt. inomatus Will, 

consobrinus Desv. magnipennis Felt. 

impatiens Walk. pinguis Walk. 

Genus CULEX Linne 
(Synonyms: Heteronycha Arribalzaga, Neoculex Dyar) 

(a) Table of the Species 

1. Feet black, both ends of some of the joints white. 

janitor Theob., pleuristriatus Theob., secutor Theob., tarsalis Coq. 
Feet uniformly blackish 2 

2. Light-colored bands of scales on the abdomen situated at the bases of 

the segments 3 

Light-colored bands located at the apices of the segments, sometimes 
almost wanting territans Walk. 

3. Upper side of the thorax dark-yellow-scaled, and usually with a small 

round dot of light-yellow scales on each side of the center; light- 
colored bands of the abdomen broad and distinct ; feet with very 
narrow, indistinct bands of light-colored scales at the sutures of the 

joints restuans Theob. 

Upper side of the thorax devoid of such dots 4 

4. Crossbands of light-colored scales indistinct on the anterior half of the 

abdomen, almost wanting on the second segment salinarius Coq. 

Crossbands distinct 5 

5. Species from the West Indies palus Theob. ; similis Theob. 

Species almost cosmopolitan pipiens Linne. 



ETIOLOGY 99 

(b) List of the Species and Synonyms 

janitor Theob. salinarius Coq. 

palus Theob. nigritulus auct. (North American 

pipiens Linne. references). 

boscii Desv. secutor Theob. 

cubensis Bigot. similis Theob. 

fatigans auct. 1 (North American tarsalis Coq. 

references). affinis Adams (not of Stephens). 

ferruginosus Wied. {Anopheles.) kelloggii Theob. 

pungens Wied. pens Speiser. 

quinquefasciatus Say. willistoni Giles, 

pleuristriatus Theob. territans Walk, 

restuans Theob. apicalis Adams. 

(c) Unrecognized Species 

flavipes Macquart, biocellatus Theobald, inflictus Theob., micro squamosus 
Theob., nigripalpns Theob., and saxatilis Grossbeck. 
(C. penafieli Williston has never been described.) 

Genus MELANOCONION Theobald 

1. Hind and other feet wholly black 2 

Hind feet white-scaled on the broad base of the fourth joint; abdomen 

black-scaled, a row of violet-scaled spots along the sides. _ (Middle 
America) urichii Coq. 

2. Thorax on the anterior half golden-yellow-scaled and with a pair of 

black-scaled spots, the posterior half black-scaled and with two stripes 

of yellow scales. (Middle America) spissipes Theob. 

Thorax wholly golden-brown-scaled 3 

3. Abdomen with bands of yellowish scales at the bases of the segments. 

(Middle America) humilis Theob. 

Abdomen unhanded 4 

4. Front angles of the segments of the abdomen yellowish-scaled. 

atratus Theob. 
Front angles and whole of the abdominal segments black-scaled. 

indecorabilis Theob., melanurus Coq. 

Genus TINOLESTES Coquillett 

Feet unicolorous black; scales of the upper side of the body black and 
with light-colored ones in the front angles of some of the segments 
of the abdomen latisquama Coq. 

Genus MICRAEDES Coquillett 

Proboscis and feet unicolorous black; scales of the abdomen purple-black 
and with light-colored ones in the front angles of some of the 
segments bisulcatus Coq. 

Genus ISOSTOMYIA Coquillett 

Proboscis, feet, and abdomen wholly black-scaled perturbans Will. 

(Aedes nigricorpus Theobald may also belong to this genus.) 

Tn response to my request, Major A. Alcock, superintendent of the 
natural history section of the Indian Museum at Calcutta, India, sent me 
specimens of this species in all the stages. The larvae have been examined 
by Dr. H. G. Dyar and Mr. F. Knab, who report having discovered differ- 
ences between them and the corresponding stage of the North American 
specimens of pipiens. 



IOO THE STUDY OF MALARIA 

Genus COQUILLETTIDIA Dyar 

(a) Table of the Species 

i. Scales of the wings mixed black and light colored, those of the costa 
not forming distinct spots ; scales of the feet black and with white 

ones at the bases of some of the joints 2 

Scales of the wings wholly black. (Middle America) 3 

2. Abdomen black-scaled and with a white band at the base of each seg- 

ment; hind tibiae with a broad light-colored band before the apex. 

perturbans Walk. 

Abdomen golden-yellow-scaled and with several black scales on the first 

three segments ; hind tibiae devoid of a distinct light-colored band. 

(Middle America) flaveolus Coq. 

3. Feet black-scaled and with white bands at the sutures of some of the 

joints, femora with a whitish spot or band at a point near three- 
fourths of their length 4 

Feet wholly black except at the base of the first joint, femora devoid 
of a distinct white mark near three-fourths of their length; abdomen 
black-scaled and with a white band or median spot at the base of each 
of the last four segments and a white spot in the front angles of 
each segment palliatus Coq. 

4. Scales on the upper side of the abdomen black and with spots of white 

ones along the sides 5 

Scales on the abdomen wholly black, on the thorax wholly brown. 

arribalzaga Theob. 

5. White spots on the sides of the abdomen situated in the front angles 

of the segments ; scales in the middle of the thorax yellow, those 

toward the sides chiefly black nigricans Coq. 

White spots on the sides of the abdomen situated near the middle of 
the segments ; scales of the thorax brown and with several lines of 
light yellow ones fasciolatus Arrib. 

(b) Unrecognized Species 

niger Giles, described from Antigua, West Indies. 

richardi Ficalbi, a European species reported from Canada by Theobald. 

(c) Species Wrongly Referred to this Genus 

antique Giles and con finis Arribalzaga belong to Grabhamia; fulvus 
Wiedemann belongs to Psorophora; sierrensis Ludlow belongs to Ochlero- 
tatus. 

Genus T^NIORRHYNCHUS Arribalzaga 

(Synonyms : Mansonia, Panoplites Theobald) 

(a) Table of the Species 

Third joint of the feet black-scaled, the base narrowly white-scaled, scales 
of the tibiae not forming distinct spots or bands titillans Walk. 

Third joint of the hind feet wholly white-scaled, black and yellowish scales 
of the tibiae collected into distinct bands and spots fascipes Coq. 

(b) List of the Species and Synonymy 

fascipes Coq. titillans Walk. 

tceniorhynchus Arrib. (not of 
Wiedemann). 

Genus AEDEOMYIA Theobald 

Proboscis with a white ring near the middle; joints of the feet white at 
at their bases ; scales of the wings brown, yellow, and white. 

squamipennis Arrib. 



ETIOLOGY IOI 

Genus ELEMAGOGUS Williston 

(a) Table of the Species 

Scales of the abdomen bluish and with a row of silvery spots along each 
side, sometimes a small median spot of white scales on some of the 
segments cyaneus Fab. 

(b) List of the Species and Synonymy 
cyaneus Fab. 

splendens Will. 

(The following two species were originally described under Hcemago- 
gus.) 

Genus CACOMYIA, new genus 

Abdomen having white scales in the middle of the last two segments only. 

albomaculatus Theob. 
Abdomen having white scales in the middle of some of the other seg- 
ments equinus Theob. 

Genus GYMNOMETOPA Coquillett 

1. Upper side of the thorax brown-scaled and with six narrow lines of 

pale yellow scales extending the entire length of the thorax ; last two 

joints of the hind feet black sexlmeata Theob. 

Upper side of the thorax not marked like this 2 

2. Last two joints of the hind feet and all the tibise black 3 

Last two joints of the hind feet chiefly white ; a spot or band of white 

scales on the base of at least the first two joints on all of the feet; 
tibiae with a silvery mark at a point about one-fourth of their 
length mediovittata Coq. 

3. With a dot of silvery scales in the middle of the front end of the 

thorax ; first two joints of the front feet white-'scaled at their bases. 

albonotata Coq. 
Without such a dot ; front feet wholly black-scaled busckii Coq. 

Genus HOWARDINA Theobald 

Feet black-scaled, the base of the first three joints of the hind ones white- 
scaled; upper side of the thorax white-scaled along the sides, the 
median portion black-scaled and with four narrow lines of pale yellow 
scales, the two middle lines united into a single line posteriorly, the 
outer two lines situated on the posterior half of the thorax. 

walkeri Theob. 

Genus PNEUMACULEX Dyar 

Thorax on the upper side velvety-brown-scaled and with six narrow lines 
of silvery scales signifer Coq. 

5. Subfamily DEINOCERITENLE Mitchell 

Genus DEINOCERITES Theobald 

(Synonym: Brachiomyia Theobald) 

(a) Table of the Species 

Proboscis and feet unicolorous blackish ; scales of the upper side of the 
body also blackish cancer Theob. 

(b) List of the Species and Synonymy 

cancer Theob. 
magna Theob. 



102 THE STUDY OF MALARIA 

6. Subfamily URANOT^NIIN^ Lahille 

Genus URANOT^ENIA Arribalzaga 

(a) Table of the Species 

i. Thorax with a median line of bluish scales ; feet wholly black 2 

Thorax without a median line; hind feet white on at least the last two 
joints and broad apex of the third 3 

2. Bluish median line of the thorax prolonged to the scutellum. 

sapphirina O. S. 
Bluish line obliterated before reaching the scutellum socialis Theob. 

3. Scutellum with blue scales ; a patch of blue scales on the thorax a con- 

siderable distance in front of the scutellum ; feet white at the sutures 

of many of the joints. (Middle America) geometrica Theob. 

Scutellum without blue scales ; no patch of blue scales on the thorax 
in front of it; feet wholly black except the last two joints and apex 
of the third in the hind ones lowii Theob. 

(b) Unrecognized Species 

apicalis Theobald and pulcherrima Arribalzaga. Both of these have been 
reported from the West Indies. 

7. Subfamily TRICHOPROSOPONIN^E Theobald 
(Synonyms : Hyloconopince Lutz, Dendromyincs Lutz, Sabettince Blanchard) 

Table of the Genera 

1. Male palpi at least one-half as long as the proboscis ; clypeus hairy. 

(Middle America) Trichoprosopon 

Male palpi less than one-fourth as long as the probiscis ; clypeus bare.. 2 

2. Veins of the wings having the outstanding scales narrow and nearly 

linear ; hind cross-vein situated at least its own length before the 

small cross-vein ; legs never fringed with scales Wyeomyia 

Veins having many rather broad outstanding scales. (Middle Amer- 
ica) 3 

3. Hind cross-vein slightly before, opposite, or beyond the small cross- 

vein, each foot bearing two claws 7 

Hind cross-vein at least twice its own length before the small cross- 
vein ; legs never fringed with scales 4 

4. With two claws on each hind foot; no scales on the posterior end of 

the thorax below the scutellum 5 

With only one claw on each hind foot in both sexes ; posterior end of 
the thorax below the scutellum bearing several broad scales in addi- 
tion to the bristles 6 

5. Proboscis shorter than the body; thickened before its apex. .Dendromyia 
Proboscis longer than the body, not thickened toward its apex. 

Phoniomyia 

6. Male proboscis strongly curved in the outer half and with a cluster of 

scales at each end of the curved portion Limatus 

7. Legs not fringed Sabethoides 

Legs fringed in places with outstanding scales in both sexes Sabethes 

Genus TRICHOPROSOPON Theobald 

(Synonym: Joblotia Blanchard) 

Feet wholly black lunata Theob. 

Feet black, the last four joints of the middle feet and the last two of the 
hind ones white nivipes Theob. 



ETIOLOGY IO3 

Genus WYEOMYIA Theobald 

Proboscis and upper side of the abdomen wholly black -scaled. 

grayi Theob., pertinans Will., smithii Coq. 

Genus DENDROMYIA Theobald 

Abdomen wholly black-scaled on the upper side ; humeri black-scaled ; first 
joint of the hind feet shorter than their tibiae. . Auteov entrails Theob. 

Genus PHONIOMYIA Theobald 

(a) Table of the Species 

Abdomen black-scaled, the front angles of the segments white-scaled. 

longirostris Theob. 

(b) List of the Species and Synonymy 

longirostris Theob. 
trlnldadensls Theob. 

Genus LIMATUS Theobald 

(Synonym: Simondella Laveran) 

Thorax golden-yellow-scaled, a median, Y-shaped spot, with the prongs 
nearest the head, and a large spot above each wing violet-blue- 
scaled durhamli Theob. 

Genus SABETHOIDES Theobald 

Abdomen black-scaled, the under side and front angles of the segments 
whitish-scaled, the white-scaled front angles prolonged so as to 
form a crossband which is interrupted except sometimes on the last 
three segments confusus Theob. 

Abdomen black-scaled, the under side whitish-scaled, and encroaching on 
the sides of the dorsum, the border of the two colors strongly undu- 
lating undosus Coq. 

Genus SABETHES Desvoidy 
(a) Table of the Species 

1. Front and hind legs not fringed 2 

Front and other legs fringed in places with outstanding scales ; middle 

legs white-scaled before and beyond the fringed portion; the broad 
apices of the hind feet chiefly white-scaled longipes Fab. 

2. Legs black-scaled, the apical part of the fringe on the middle legs white. 

nitldus Theob. 
Legs wholly black-scaled locuples Desv. 

(&) List of the Species and Synonymy 

locuples Desv. longipes Fab. 

remipes Wied. nitidus Theob. 

The hatching of the first brood of anophelines bears an inti- 
mate relation to the seasonal occurrences of malaria. The 
seasonal variations of different species are probably dependent 
upon the presence or absence of breeding pools suitable to 
particular species. Temperature also exerts an influence, the 
hibernating females of some species leaving winter quarters 



104 THE STUDY OF MALARIA 

earlier than others, and hibernating larvae mature at different 
temperatures. 

While the anophelines are mosquitoes of low altitudes, they 
may be found at considerable elevations. Thus in the Alps 
they are found at an altitude of 1,145 metres; in the Ap- 
penines at 1,283 metres; in Java at 1,000 metres; at Harrar 
at 2,000 metres ; in Africa at 1 ,900 metres, and in the high 
plateaus of Mexico at 2,000 metres. 1 ' 15 

It is the rule among mosquitoes that only the females are 
blood suckers, hence it is this sex alone that is concerned in 
the propagation of malaria. The female insects suck not only 
the blood of man, but of other mammals, birds, occasionally 
of cold-blooded animals, and even other insects. Blood is 
necessary for both the procreation of mosquitoes and the devel- 
opment of the sexual cycle of the malarial organism. While 
both sexes have the blood-sucking apparatus, the puncturing 
portion of the proboscis of the male is much weaker than that 
of the female. 

There are a few exceptions to the rule that males do not 
bite. While males do not infrequently light upon the skin and 
probe around with the proboscis, they usually fly away without 
partaking of blood. But the male Stegomyia fasciata has been 
known to bite. Doctor Stiles m4 is said to have been bitten by 
a male Culex nemoralis, and the male of Culex elegans is said 
by Sambon 1,21 to be quite as bloodthirsty as the female. The 
habitual diet of male mosquitoes, however, is vegetarian. They 
are very fond of fruits, as bananas, dates, pears, apples, melons, 
and of the nectar of flowers, wine, and beer. In captivity mos- 
quitoes may be kept alive for some days upon a diet merely 
of sweetened water. 

Anopheline mosquitoes rarely suck blood except during the 
night. After feeding they usually retire to remote and dark 
corners or to breeding places to oviposit. Persons may be 
bitten during sleep without being disturbed, since these insects 
are not noisy and their bite is not particularly painful. During 
the day their reserved habits make them difficult of detection. 
They will ordinarily feed in a few hours after hatching; in 
captivity, however, it may be difficult to induce them to feed 



ETIOLOGY 105 

upon blood. The meal is repeated, as a rule, once every day 
or every few days. Blood is essential for the maturation of 
fertile ova, one feeding being sufficient for one oviposition. 
The act of biting (Fig. 40) has been described as follows: 
"When the female anopheles bites the proboscis is pointed 
downwards and the labellse are pressed against the skin of the 
victim. The labrum, the hypopharynx, the mandibles, and the 
maxillae are pressed together into one solid boring instrument, 
like the parts of a trocar. Their common tip is forced down at 
the angle between the spread labellse, which serve to hold and 
direct these clustered parts. Whilst the piercing organs pass 
into the tissues the labium bends backwards at about a third 
from its base, and its angle, pointing towards the breast of the 
insect, becomes more and more acute with the deepening of the 




\ I 

Fig. 40. — A female mosquito in the act of biting. 

mouth parts. The palpi, which usually lie parallel with the 
proboscis, are raised and diverged during puncture." 121 

The buzzing note of the mosquito is produced by the vibra- 
tions of the chitinous shreds within the large tracheae and not 
by the wings, as commonly supposed. As Howard 122 states, 
there is quite a difference between the note of Anopheles 
maculipennis and that of the common species of culex, the note 
of the latter being high in pitch, that of the former being sev- 
eral tones lower. 

A point of great practical interest is the length of flight of 
the mosquito and the extent to which it may be borne by the 
wind. It is a general rule that mosquitoes do not migrate far 
from their native pools or from dwellings where nourishment 
may be obtained. 

It is very unusual for anophelines to fly farther than a few 
hundred yards, and half a mile may be regarded as the maxi- 



Io6 THE STUDY OF MALARIA 

mum limit of flight. They are poorer flyers than most other 
species. For this reason they are less often borne by the wind, 
since they seek shelter when a breeze arises. While the wind 
is not so generally a vehicle for the dissemination of mosquitoes 
as commonly believed, certain species, especially of salt water 
breeders, are borne by the wind for several miles. The greater 
prevalence of mosquitoes in dwellings after a wind may often 
be due to their retiring thither for protection. Mosquitoes may 
be carried in wagons loaded with straw, hay, or fruit, and 
upon railroad cars. Many localities formerly free from the 
pests date their affliction with mosquitoes from the introduction 
of railroads. Vessels may not only transport the insects for 
great distances, but may even afford breeding places. 

The preference of anophelines for certain colors has been 
demonstrated by Nuttall. 123 . Boxes lined with cloth of differ- 
ent colors were placed where the mosquitoes were plentiful, 
and on seventeen days the number on each box was counted, 
with the following result: 

p. , f , Number of A nopheles malculipennis counted 

^oior or dox. in eacll bf>x dur ; ng seventeen days. 

Navy blue 108 

Dark red 90 

Brown, reddish 81 

Black 49 

Scarlet 59 

Slate gray 31 

Dark green (olive) 24 

Violet 18 

Leaf green 17 

Blue 14 

Pearl gray 9 

Pale green 4 

Light blue 3 

Ochre 2 

White 2 

Orange 1 

Yellow ._. 

"512 

Galli-Valerio and De Jongh 124 counted 119 anophelines rest- 
ing upon dark colors and 33 upon bright colors, and 349 culex 
upon dark colors and 120 upon bright. 

Mosquitoes are fond of the odor of leather and are usually 
plentiful upon harness hanging in stables. They are said to 
prefer the odor of the negro to that of the white man. 



ETIOLOGY 107 

Anophelines, like other malefactors, prefer darkness rather 
than light, and seek the sequestered nooks during the day. 

A meal of blood is a prerequisite to fertilization. Females 
confined with males, then isolated and fed, do not deposit 
fertile eggs, but must be fed first. A single fertilization is 
sufficient for several batches of eggs. These are usually de- 
posited between dusk and dawn. Still water is necessary, since 
the female may be drowned if the surface is agitated. The 
female sits upon the water or upon the edge of floating leaves 
or debris. The ova of anophelines are deposited upon the 
water in clumps, but soon separate and lie horizontally. A 
batch of ova usually numbers from 100 to 150. Pressat 125 
has calculated, on a basis of 150 ova for each female, hatching 
50 per cent, females, that a single female in one season pro- 
duces about five billion mosquitoes. 

Parthenogenesis has occasionally been observed in mosqui- 
toes. Kellogg 114 reared a female mosquito from the pupa 
which almost immediately deposited eggs; she had not been 
fertilized. Larvae developed from the ova and nearly reached 
full growth before dying. Unfertilized female Stegomyia 
fasciata and Culex pipiens have also been known to deposit 
ova, which, however, were not fertile. 

It is impossible to determine the length of life of mosquitoes 
in nature, though even in captivity they have been kept for 
weeks. Anophelines have been kept alive five days with- 
out food or water, and for about two months fed upon 
bananas. The males are not so long lived as the females. 
Mitchell 126 has kept Stegomyia fasciata sixty-one days. It is 
well known that mosquitoes survive long droughts, as well as 
hibernate. 

Stephens and Christophers 118 say there is evidence that the 
ova can survive for some months in moist earth and exposed 
to frost. Eysell 127 and Galli-Valerio and De Jongh 124 state 
that the ova of most species of mosquitoes of the northern 
temperate and frigid zones may hibernate. 

Mosquitoes hibernate in the larval stage also. Smith 114 
found, in New Jersey, larvae of Culex pun gens in ice contained 
in pitcher plants, and believes that larval hibernation must be 



108 THE STUDY OF MALARIA 

extremely common. Mitchell 126 found anopheles larvae in 
tanks and barrels in the Botanical Gardens of Washington, 
D. C, during winter, and Woldert 128 found these larvae in 
December at Tyler, Texas. 

Mitchell 126 believes it probable that mosquitoes do not hiber- 
nate in the pupal stage, though Galli-Valerio and De Jongh 124 
maintain the opposite opinion. 

It is chiefly in the winged stage that mosquitoes hibernate. 
In the late fall the males die, the fecundated females seeking 
shelter in dwellings, cellars, stable, barns, cisterns, hollow trees, 
or under bridges. Annett and Dutton 129 thus describe the 
hibernation of Anopheles maculipennis in England: 

1. The attitude is peculiar, the insect lying quite flat upon 
the surface with its legs spread out. In this position the under 
surface of the thorax touches, or nearly touches, the wall. 

2. Only females are found, and these are always fertilized, 
and have the spermatheca filled with spermatozoa. 

3. The insects are difficult to arouse and very sluggish in 
any movements they make. . 

4. They do not feed unless the temperature is raised. If 
kept at a low temperature (provided the air is moist) they 
remain for weeks without feeding. 

5. If aroused by raising the temperature they feed readily 
and the ovaries rapidly develop. Eggs are laid, and in most 
cases the female dies after their deposition. 

Study of Mosquitoes. — To obtain adult mosquitoes they 
may be either captured or bred from larvae. Mosquitoes are 
best captured by placing very carefully the mouth of a test 
tube or bottle over the insects while resting. They are killed 
preferably by the cyanide bottle, by chloroform, or by tobacco 
smoke. The cyanide bottle is prepared by placing in the bot- 
tom of a wide-mouthed bottle a number of small pieces of 
potassium cyanide and covering with liquid plaster of Paris. 
When the plaster has hardened the bottle is ready for use, and 
should then be kept tightly corked, as the fumes are poisonous. 
Mosquitoes should not be killed immediately after hatching, 
as the exoskeleton is then soft and marked shrivelling occurs. 
A net should not be used for capturing adult mosquitoes, for 



ETIOLOGY IO9 

the delicate scales are thereby worn off and the specimen 
spoiled. 

Mosquitoes should be mounted as soon as killed, since the 
legs soon lose their pliability and are apt to be broken off. 
The materials needed for mounting are fine entomological 
pins, No. 00 ; ordinary black or mourning pins, and cardboard 
slips. These latter may be cut oblong, one-half by 1 inch, or 
circular, using a 16 or 20-gauge wad-cutter. One of the fine 
pins is run for two-thirds of its length through one of the 
cardboard slips. The mosquito, lying upon its back upon a 
piece of cork, is transfixed by the point of this pin through 
the center of origin of the legs. One of the larger pins is now 
run through the cardboard in an opposite direction, and when 
stuck into the cork lining of the cabinet serves as a support. 




Fig. 41. — A pinned specimen. 

Naphthaline or camphor should be placed in the cabinet to 
exclude mites. 

Parts of mosquitoes, the wings, legs, antennae, scales, etc., 
may be mounted upon slides. A ring of varnish should be 
made upon a slide and the object placed in the center of this 
ring, the cover-glass pressed down gently and its edge ringed, 
preferably with Damar. 

Ova, larvae, and pupae may be mounted in concave slides or 
upon slides having a cell made by ringing with varnish. In 
this cell the object is mounted with Farrant's medium or with 
10 per cent, solution of formalin, and the edge of the cover- 
glass ringed. 

In order to catch larvae the only implements required are 
a white enamelled dipper, a spoon, and a container for the 
wrigglers when captured. To "breed out" larvae they should 
be placed in wide-mouthed jars half filled with water and a 



IIO THE STUDY OF MALARIA 

layer of sand in the bottom, and covered with gauze held in 
place by means of a rubber band. The larvse in each jar 
should be near the same size, otherwise the larger will devour 
the smaller ones, and they should not be too numerous. A 
few grains of dry rice should be dropped in for food. 

Adults also should be kept in such jars, which should, how- 
ever, contain only a small quantity of water, upon which 
should float a thin sheet of cork, and each jar should contain 
a slanting strip upon which the insects may rest. A bent 
hairpin makes a good hook upon which to suspend a piece of 
fruit from the edge of the jar. 

In order to infect mosquitoes with malaria they must, of 
course, be fed upon blood containing parasites. They may 
be fed by holding the moistened forearm against the gauze 
covering of the jar or they may be placed in cages covered 




Fig. 42. — Stomach of infected mosquito. 

with wire netting, one end of which has an opening protected 
by a sleeve through which the arm may be introduced. The 
mosquitoes should be fed in twenty-four to forty-eight hours 
after hatching and thereafter every day for several days. 

In investigating the mosquito cycle of the parasite of mala- 
ria the sexual forms must be sought for in the midgut or 
stomach, and the sporozoits in the salivary glands. 

In the dissection of the midgut proceed as follows : 

Do not dissect the mosquito until the blood from the last 
feeding is digested, which may be ascertained by the disap- 
pearance of the dark color on the lower surface of the abdo- 
men. 

Kill the mosquito by means of cyanide fumes, chloroform, 
ether, or tobacco smoke. 

Pull off the wings and legs and remove the scales with a 
small camel's-hair brush. 



PLATE I 




A miniature mosquito farm. 



ETIOLOGY 



III 



Place, with the ventral aspect up, in a drop of normal salt 
solution upon a glass slide. 

Transfix the center of the thorax with a dissecting needle. 

Flatten the abdomen by gentle pressure of the other needle, 
and nick the intersegmental membrane on each side between 
the second and third last segments. 




Fig. 43. — Midgut, Malpighian tubules, and ovaries of the mosquito. 

With the needle upon the last segment, pull gently until the 
segments separate and the viscera are drawn out. 

Separate the stomach from the esophagus in front and from 
the hind-gut and Malpighian tubules behind, and remove these 
organs. 

Add more salt solution if necessary and apply a cover-glass 

The salivary glands (Fig. 44) lie immediately above the 
origin of the first pair of legs. One method of removing them 




Fig. 44. — Dissection of the salivary glands (after Daniels). 

is to transfix the posterior portion of the thorax with one 
needle and with the other pull off the head, when the salivary 
glands and a tag of the esophagus are dragged out. Another 
method is, after removing the wings and legs, to cut off the 
head and to make an incision parallel to the anterior border of 
the thorax and on a level with the middle pair of legs. The 
glands are teased out of this segment after first cutting the 
exoskeleton in several places. They are recognized as trans- 
lucent glistening bodies. 



112 THE STUDY OF MALARIA 

THE PARASITES OF MALARIA 
Zoological Relations. — The parasites of malaria belong to 
the animal kingdom, to the division of protozoa, to the class 
of sporozoa, and to the order of hemosporidia. The hemo- 
cytozoa are not peculiar to man, but are found in other classes 
of vertebrates, and are distributed by Manson 59 into three 
genera, as follows : 

H^MOCYTOZOA 
i. Genus H^emamceba 
Names. Hosts. 

H. subtertiana. The malaria parasites of man, the sexual 

H. tertiana. phase being evolved in mosquitoes of 

H. quartana. the genus Anopheles. 

H. relicta (Proteosoma). Birds; sexual phase in mosquitoes of 

the genus Culex. 

H. Danielewski (Halteridium). Birds. 

H. Kochi. Several species of monkeys. 

H. melaniphera. Bat (Miniopterus Shreibersii). 

H. Metchnikovi. Trionyx indicus. 

2. Genus Piroplasma 



P. bigeminum. 


Bovines ; transmitted by the cattle tick 




(Boophilus bovis). 


P. canis. 


Dogs. 


P. ovis. 


Sheep. 


P. equi. 


Horse. 


P. hominis. 


Man. 


3. Genus 


H^MOGREGARINA 


H. ranarum (Drepanidium). 


Frog (Rana esculenta). 


H. splendens. 


Frog (Rana esculenta). 


H. magna. 


Frog (Rana esculenta). 


H. lacertarum. 


Lizard (Lacerta muralis). 



About twenty additional but less readily procured species. 

There are three sharply defined species of parasites of mala- 
ria, the parasite of tertian malaria, the parasite of quartan 
malaria, and the parasite of estivo-autumnal malaria. The 
latter is divided by most observers into three, or at least two, 
varieties, the tertian and the quotidian, of which latter variety 
a pigmented form and an unpigmented form are described. 
The writer's opinion is that there are two varieties of the 
estivo-autumnal parasite, the tertian and the quotidian, and 
that the pigmented and the unpigmented quotidians are merely 
forms of one variety. 



ETIOLOGY 



"3 



A number of students of malaria, with Laveran at their 
head, maintaining the unity of the malarial parasites, hold 
that the several species are only forms of one species which 
may be mutually transformed. The arguments upon which 




Fig. 45. — Diagram illustrating the cycles of the parasite. 
— . — . — . — . Schizogonic cycle. 

Sporogonic cycle. 

Parthenogenetic cycle. 

their theory is based are so unsound in the light of our present 
knowledge that it is unnecessary to review them. 

Biology. — The life history of the parasites of malaria is 
somewhat complicated, inasmuch as man, the mosquito, and 



114 THE STUDY OF MALARIA 

the parasite are involved, and as there are three species of 
parasites and each species has three biologic cycles. These 
three cycles are : 

1. The' schizogonic, or human cycle, also called the asexual 
cycle, monogonic cycle, endogenous cycle, cycle of Golgi, or 
trophic cycle. 

2. The sporogonic or mosquito cycle, also called the sexual 
cycle, amphigonic cycle, exogenous cycle, or cycle of Ross. 

3. The parthenogenetic cycle, or reproduction by unfertilized 
macrogametes ; the cycle of chronic malaria, of latency and re- 
lapses, an immaculate conception yielding saviours to the spe- 
cies necessary for its salvation at a time of crisis, a vicarious 
atonement of macrogametes that the human cycle may be 
saved. 

The first cycle is that of active malaria; the last two are 
destined for the perpetuation of the species, and without them 








Fig. 46. — The entrance of the sporozoit into the red cell. 

the interruption of the schizogonic cycle would result in the 
extermination of the species. 

The Schizogonic Cycle. — In the act of biting the mosquito 
injects into the blood sporozoits, elongated or needle-shaped 
organisms. The sporozoits have the power of bending, con- 
traction, and of locomotion, and each immediately penetrates 
into a red blood-cell (Fig. 46). Here it loses its slender form 
and appears as a mere dot of protoplasm, whose index of re- 
fraction varies but little from that of the red cell. The size 
of the young parasite varies in different species, but is about 
1 or 2 microns in diameter. Ameboid motion is more or less 
active, pseudopodia being protruded and retracted, the parasite 
even changing its position within the cell, and has no constant 
form. There is usually only one parasite in each infected cell, 



ETIOLOGY 



"5 



but there may be several. As the parasite grows it acquires 
pigment, a few grains at first, gradually increasing in amount 
with the growth of the parasite. This pigment is from the 
hemoglobin of the infected cell, and occurs in the form of 
grains, rods, or clumps. The adult parasite occupies a rela- 
tively large portion of the cell, and ameboid motion is less 
active, though the pigment may be in violent motion. The 
organism is composed of cell protoplasm, nucleus, and nucle- 
olus, but appears structureless in fresh, unstained blood. Prior 
to sporulation the pigment becomes concentrated and fused, 
and fission occurs, dividing the parasite more or less symmetri- 
cally into spores, constituting the so-called rosette or mar- 
guerite forms, each spore containing a fragment of nucleus. 






& 



Fig. 47. — Diagram representing the development of the malarial parasite : a, Young 
form ; b, half-grown parasite ; c, sporulating body ; d, free spores ; e, macrogamete ; 
/, microgametocyte. 




The cell ruptures and the spores, or merozoites, escape into the 
blood current, where they rapidly enter the blood-cells to repeat 
the cycle. The corpuscular remnants and the pigment are 
rapidly taken up by the phagocytes. 

Instead of proceeding to sporulation some of the parasites 
develop into sexual forms, or gametes, large parasites of round, 
ovoid, spindle, or crescentic shape. It is these bodies which 
are taken up by the mosquito, undergo a sexual cycle in its 
midgut, develop into sporozoits, which are injected into man, 
where they pass through the schizogonic cycle above outlined. 

The Tertian Parasite (Hcemamceba vivax, H. tertiance, 
Plasmodium vivax). — The duration of the asexual cycle of 
the simple tertian parasite is forty-eight hours. The young 



Il6 THE STUDY OF MALARIA 

parasites are about one-fifth the size of the red blood corpus- 
cles and unpigmented. They are difficult to distinguish from 
the young parasites of the other species. They are actively 
ameboid, protruding and retracting short pseudopodia with 
rapidity; Y-shapes, T-shapes, and crosses are common forms. 
The index of refraction of the parasites is low, so that their 
contours are not clearly distinguished from the substance of 
the red blood-cells. As the parasite increases in size pigment 
gradually appears. The pigment of the tertian parasite is fine, 
rod-shaped, rather light in color, and in active motion. This 
motion of the pigment has been compared to the bubbling of 
boiling water and to the swarming of insects. The infected 
red cell becomes enlarged, swollen, and pale. The half -grown 
parasite fills about half or two-thirds of the red blood cor- 
puscle. At this stage the parasite assumes fantastic and bizarre 
shapes. The adult parasite is more or less spherical, as large 
as or larger than a normal red cell, and occupies three-fourths 
or four-fifths of the swollen infected cell, the margin of which 
may be difficult to see on account of its pale color. The pig- 
ment tends to become more abundant about the periphery. 
When sporulation is imminent the parasite and its pigment 
becomes less active or motionless, the pigment gathers in 
clumps at the center, and radial striations appear from the 
periphery toward the center. Usually the sporulating tertian 
parasite is not so symmetrical as the corresponding stage of 
the quartan, resembling, rather, a bunch of grapes or a mul- 
berry. Less often there are two concentric rows of spores. 
The spores are small and oval and vary in number from twelve 
or fourteen to twenty-six, oftenest sixteen, and more often an 
even than an uneven number. Sporulation takes place espe- 
cially in the circulation of certain viscera, but sporulating ter- 
tian parasites are much more frequently encountered in the 
peripheral circulation than in the case of estivo-autumnal infec- 
tions. 

The parasites develop with remarkable uniformity, nearly 
all appearing to be of the same age. Even in infections with 
two groups of tertian parasites, which is very common, it is 
unusual to find a parasite which does not belong to one brood. 



DESCRIPTION OF PLATES II AND III 



Various forms ot malarial parasites: Figs, i to 10 inclusive, tertian parasites; 
Figs, ii ta 19 inclusive, quartan parasites; Figs. 20 to 26 inclusive, estivo- 
autumnal parasites. 

1. — Normal red blood cell. 2. — Young tertian ring. 3. — Large tertian ring. 
4. — Half-grown tertian parasite. 5. — Infected cell showing Schiiffner's dots. 
6. — Adult tertian parasite. 7. — Beginning sporulation. 8. — Sporulation com- 
pleted. 9. — Tertian microgametocyte. 10. — Tertian macrogamete. 11. — Young 
quartan ring. 12. — Older quartan ring. 13. — Quartan band. 14. — Older 
quartan band. 15. — Full-grown quartan parasite. 16. — Mature parasite with 
divided chromatin. 17. — Sporulation completed. 18. — Quartan microgameto- 
cyte. 19. — Quartan macrocyte. 20. — Young estivo-autumnal ring. 21. — Large 
estivo-autumnal ring. 22. — Mature parasite. 23. — Sporulation completed. 
24. — Estivo-autumnal microgametocyte. 25. — Estivo-autumnal macrogamete. 
26. — Estivo-autumnal ovoid. 






PLATE II 



o 



• # t ♦ • \t - ^ 



8 



'♦A'\ 



■^■W«v" * ■'■■-■■ 



o C 



10 U « 

Deaderick Del. 



PLATE m 



** T •. W 1 

i ./' J. '. ,r 



L-'a.'- (, \ 



J3 



14 



15 






■^■i 
*.•«»* 



*v ; 






16 



17 



18 



19 



o 



20 



21 



22 






•'.**. 

-•-V*' 

■'f' 









23 



24 



25 



26 

Deaderick Del. 



ETIOLOGY 117 

The early development of the gametes is not well under- 
stood. Half-grown gametes are hard to differentiate from 
schizonts, but small parasites, without ameboid motion, with 
much pigment, and with large nucleus may be regarded as 
gametes. The adult gamete resembles the full-grown schizont. 
In shape it is more or less spherical and may be twice as large 
as a red blood corpuscle. Ameboid movement is very slight, 
the pigment is profuse, fine, reddish, or blackish, and actively 
motile. The vesicular appearing nucleus is commonly situated 
near the periphery, and is visible in fresh preparations. 

An interesting phenomenon which occurs in the case of the 
microgametocytes, or male sexual forms, is exflagellation. 
This takes place from ten to thirty minutes after the blood has 
been withdrawn, and is favored by exposing the blood for 
a few minutes to the air, by the addition of a minute quantity 
of water, and exposure to moisture, as breathing upon the 
slide before applying the cover-glass. Before exflagellation 
the pigment is observed to undergo violent and tumultuous 
motion, then to collect toward the center. Undulations at the 
periphery are then noted, as if something within were trying 
to escape. Suddenly the fiagella break forth from different 
points of the margin. These are from four to eight in number 
and in length are two and a half to three times the diameter of 
the red blood corpuscle. They may show ovoid swellings at 
the end or in their continuity. Lashing madly to and fro, the 
red cells are displaced and a flagellum may be seen to break 
off from the microgametocyte and dart in a serpentine manner 
among the cells. The fiagella are known as microgametes, 
and have been shown by McCallum to be spermatozoa. Their 
function is to fertilize the macrogametes, or female forms, in 
the midgut of the mosquito. 

Tertian gametes may be distinguished from adult schizonts 
by the former being of larger size, less ameboid motion, their 
pigment appearing earlier, being more abundant and in more 
active motion. 

The following may serve to differentiate tertian male and 
female gametes : 



1 1 8 THE STUDY OF MALARIA 

Micro gametocytes. Macrogametes. 

Plasma hyaline. Plasma granular. 

Pigment abundant, in thick rods, Pigment in fine rods and granules, 

brownish yellow. brownish black. 
Not larger than a red blood-cell. Larger than a red cell. 

Chromatin profuse. Chromatin less abundant. 

Little ameboid motion. More or less ameboid motion. 

Nucleus toward center. Nucleus toward periphery. 

In stained films the early stage of the tertian parasite is 
seen as a ring. Often the ring is not of the same thickness 
throughout its circumference, but is composed of a thin seg- 
ment, and a thicker segment, the chromatin, being upon the 
thin segment. Usually the chromatin dot is immediately within 
the ring, but may lie outside, and is surrounded by a pale zone. 
The achromatic zone may be regarded as the nucleus and the 
chromatin as the nucleolus. As the parasite develops one arc 
becomes much thickened, giving the appearance of the signet 
ring. The forms of the half-grown parasite are varied and 
peculiar. Pigment appears first and most abundantly in the 
peripheral region, and does not invade the clear zone. The 
red cell is enlarged and does not stain deeply. A peculiar 
stippling of the infected red cells is shown in films containing 
tertian parasites and stained with the Romanowsky stain or 
one of its modifications. When the parasite fills one-third of 
the cell a number of fine, red-stained points, Schuffner's dots, 
appear, which increase in size but not in number as the parasite 
grows. In the process of sporulation the chromatin becomes 
subdivided and surrounded by a clear zone and encircled by 
the blue cytoplasm, constituting the spore. 

The Quartan Parasite (Hccmamccba malaria:, H. quartana, 
Plasmodium malaria, Laverania malaria;). — : The duration of 
the schizogonic cycle of the quartan parasite is seventy-two 
hours. The young forms of the parasite appear as small, 
hyaline, unpigmented bits of protoplasm. They are highly 
refractive and the contour is much more sharply defined than 
the tertian parasite. Ameboid motion is sluggish and the 
organism may be watched some time until motion is detected. 
Pigment appears within twenty-four hours. It is in larger 
quantities than in the tertian parasite, in coarser grains or rods, 
and dark brown or black in color. The pigment is accumu- 



ETIOLOGY 119 

lated around the margin, and its motion is very slow. In the 
half-grown parasites the peculiar forms observed in the tertian 
organisms are not seen, and ameboid movements become more 
sluggish or cease altogether. The red blood-cell infested with 
the quartan parasite does not enlarge and decolorize as in 
tertian infections, but, if there is any deviation from normal, 
becomes smaller and darker, perhaps greenish and brassy. The 
adult parasites are almost as large as the red cells. Prior to 
sporulation the pigment collects toward the center, often in 
a radial arrangement. Sporulation proceeds after the manner 
of the tertian parasite, but is slower. The sporulating forms 
are beautifully symmetrical, and are typical rosettes. The 
spores are round or oval, relatively large and six to twelve in 
number, oftenest eight. Sporulating quartan parasites are 
much more commonly observed in the peripheral blood than 
are the corresponding forms of the other species. 

Quartan gametes are but rarely encountered. The macro- 
gametes are spherical in shape, and as long as they remain 
intracorpuscular are smaller than tertian gametes, but are 
equally, as large when they become extracorpuscular. Ex- 
flagellated microgametocytes have been observed; they are 
somewhat smaller than the tertian forms, but no less active. 

The staining reactions of the quartan parasite are similar 
to those of the tertian. The young form is a ring and so 
closely resembles the tertian that it cannot be distinguished with 
certainty. After twelve to twenty-four hours the parasite be- 
comes disc or band shaped. The latter forms are character- 
istic. The parasite extends across the center of the infested 
cell as a more or less broad band, often rather quadrilateral, 
the pigment being arranged more profusely along the margin 
of the band. The chromatin body of the quartan species stains 
less intensely and splits earlier than in the tertian. The adult 
usually fills the corpuscle, which may be no longer apparent. 
The sexes of the gametes are differentiated by the same char- 
acters as in the tertian. 

The Estivo-autumnal Parasite {Hcemamceba precox, 
Plasmodium precox, Hamamoeba immaculata, Laverania pre- 
cox, Hcemomenas prcecox, Plasmodiwm immaculatum, Hczma- 



120 THE STUDY OF MALARIA 

mceba parva, Hcsmatosoon falciform, Plasmodium falciparum) . 
— The young forms of the estivo-autumnal parasites are similar 
to those of the other species, but are smaller, being from one- 
fifth to one-sixth the size of the infested corpuscle. Ameboid 
motion is rather active, stars, crosses, and irregular shapes 
occurring in succession. At rest the parasites appear annular 
or discoid. More than one parasite in a single cell is rela- 
tively more common than in tertian and quartan infections. 
Advanced stages of development are rarely seen in peripheral 
blood. The infested red cells often become shrivelled, cre- 
nated, darker, and of a brassy hue. The adult parasites do 
not attain the size of the red blood corpuscles. Sporulation 
proceeds in a manner similar to that of the simple tertian 
parasite. The spores number from five to twenty-five or even 
thirty. Sporulation is not so uniform as in the other infec- 
tions; sporulating forms may be associated with young or 
half -grown parasites. 

Estivo-autumnal gametes occur in the form of crescents, 
and of fusiform, ovoid, and spherical bodies. The crescent is 
characteristic, being found in this form of malaria alone. They 
are cylindrical, tapering slightly at each extremity, and 
slightly curved upon themselves. They are longer than the 
diameter of the red cell and about a third as broad as long. 
The changes from crescent to ovoid and round bodies may 
be easily observed under the microscope. The gametes appear 
only after the infection has persisted for about a week. The 
crescent may lie within the cell or may have the appearance 
of the red cell being attached to the concave side; in some 
instances there is no evidence left of the infested blood-cell. 
The cell may be stretched across the concavity of the crescent, 
and is usually almost decolorized. The crescents have given 
evidence of a double outline. They possess no ameboid move- 
ment, and the pigment in the form of rods or granules is 
motionless. Before exflagellation the crescent assumes the 
spherical form, smaller than the tertian, and similar to the 
quartan. 

The staining reactions of the estivo-autumnal schizonts are 
similar to those of the tertian and quartan. The young para- 



DESCRIPTION OF PLATES IV AND V 1 



The drawings were made with the assistan of the camera lucida from specimens of fresh 
blood. A Winckel microscope, objective % (oil immersion), ocular 4, was used. Figures 4, 13, 23, 
24, and 42 of Plate IV were drawn from fresh blood, without the camera lucida. 

PLATE IV 

The Parasite of Tertian Fever. 

1.— Normal red corpuscle. 

2, 3, 4.— Young hyaline forms. In 4, a corpuscle contains three distinct parasites. 

5, 21. — Beginning of pigmentation. The parasite was observed to form a true ring by the con- 
fluence of two pseudopodia. During observation the body burst from the corpuscle, which became 
decolorized and disappeared from view. The parasite became, almost immediately, deformed and 
motionless, as shown in Fig. 21. 

6, 7, 8.— Partly developed pigmented forms. 
9.— Full-grow h body. 

10-14.— Segmenting bodies. 

15. — Form simulating a segmenting body. The significance of these forms, several of which 
have been observed, was not clear to Drs. Thayer and Hewetson, who had never met with similar 
bodies in stained specimens so as to be able to study the structure of the individual segments. 

16, 17.— Precocious segmentation. 

18, 19, 20.— Large swollen and fragmenting extracellular bodies. 

22— Flagellate body. 

23, 24.— Vacuolization. 

The Parasite of Quartan Fever. 

25.— Normal red corpuscle. 
26. — Young hyaline form. 

27-34.— Gradual development of the intracorpuscular bodies. 

35.— Full-grown body. The substance of the red corpuscle is no more visible in the fresh 
specimen. 

36-39.— Segmenting bodies. 

40.— Large swollen extracellular form. 

41.— Flagellate body. 

42.— Vacuolization. 

PLATE V 
The Parasite of ^Estivo-autumnal Fever. 

1, 2.— Small refractive ring-like bodies. 

3-6.— Larger disk-like and ameboid forms. 

7.— Ring-like body with a few pigment-granules in a brassy, shrunken corpuscle. 

8, 9, 10, 12.— Similar pigmented bodies. 

11.— Ameboid body with pigment. 

13. — Body with a central clump of pigment in a corpuscle, showing a retraction of the hemo- 
globin-containing substance about the parasite. 

14-20. — Larger bodies with central pigment clumps or blocks. 

21-24.— Segmenting bodies from the spleen. Figs. 21-23 represent one body where the entire 
process of segmentation was observed. The segments, eighteen in number, were accurately 
counted before separation, as in Fig. 23. The sudden separation of the segments, occurring as 
though some retaining membrane were ruptured, was observed. 

25-33.— Crescents and ovoid bodies. Figs. 30 and 31 represent one body, which was seen to 
extrude slowly, and later to withdraw, two rounded protrusions. 

34, 35. — Round bodies. 

36.—" Gemmation," fragmentation. 

37. — Vacuolization of a crescent. 

38-40. — Flagellation. The figures represent one organism. The blood was taken from the ear 
at 4.15 p. m. ; at 4.17 the body was as represented in Fig. 38. At 4.27 the flagella appeared ; at 4.33 
two of the flagella had already broken away from the mother body. 

41-45.— Phagocytosis. Traced with the camera lucida. 

1 These illustrations are reproduced by permission from the article by Drs. Thayer and Hewet- 
son in The Johns Hopkins Hospital Reports, vol. v., 1895. 



PLATE IV 

The Parasite of Tertian Fever. 






>**•■„ ^i% 



% 
# 



















fg^vh 



■i'o 


tff 3T*** 


/■'if ' .*■ 


"-i/^-^"*'":^,. 




? V , V.Vf 



^ 






The Parasite of Quartan Fever, 



V.-.'*' t-f- 




¥ 


^ 


„•_ . 




> 


-* 



25 



28 



£5 



? '\ 



■a. 






32 



33 






34- 






35 



■iCT'V. 



36 






30 



40 



41 



f 



+e 



5& 



$ 



•• 









* * ^ *., 



PLATE V 

The Parasite of Aestivo Autumnal Feven 



10 



20 



Zi 



22 



23 



2* 



25 



27 



23 



29 



30 



32 



33 



3* 



35 



36 



o 



o 



37 






•*r 



38 






39 



40 






O 



4a 



« 



4+ 






« 



*0 



ETIOLOGY 



121 



sites are unpigmented rings, resembling the simple tertian 
rings, but are smaller and more delicate. Typical signet rings 
and rings without nodes are seen. The ring may be distorted 
or become broken and extended like a delicate thread or a 
narrow band. The largest rings are about one-half the diam- 
eter of the red cell. The pigment is sparse. Both the sporu- 
lating body and the individual spores are small. The central 
region of the crescent is almost achromatic, the extremities 
staining more deeply. Chromatin is not always visible in the 
crescents, but is usually seen, as is the pigment, in the achro- 
matic area. 

Mixed infections with quotidian and tertian estivo-autumnal 
parasites are very common. 

The differences between these parasites are thus tabulated 
by Craig: 70 



The Hyaline Body 



Stage of Develop- 
ment. 


Quotidian. 


Size. 


Minute, one-sixth of 




corpuscle. 


Shape. 


Ring or perfectly round. 


Outline. 


Indistinct. 


Motion. 


Very active. 


Corpuscle. 


Very dark green, wrin- 




kled. Crenated. 


Number. 


More than one parasite 




in a corpuscle, com- 




mon. 



Malignant Tertian. 

Larger, one-third to one- 
quarter of corpuscle. 

Signet-ring shape. 

Clear cut and refractive. 

Sluggish. 

Light green, less wrin- 
kled. 

Very seldom more than 
one parasite in a cor- 
puscle. 



Size. 
Shape. 

Motion. 
Outline. 

Pigment. 

Number. 
Corpuscle. 



The Pigmented Body 

One-quarter size of cor- 
puscle. 

Round. Loses ring form 
before pigmentation. 

Ameboid motion is lost. 

More sharply defined. 



One or two coarse gran- 
ules, perfectly motion- 
less. 

May be more than one 
in a corpuscle. 

Very green in color, 
often crenated. 



One-half size of corpus- 
cle. 

Ring form becomes pig- 
mented, afterward the 
parasite is round. 

Ameboid motion con- 
tinues. Is sluggish. 

Very sharply defined and 
refractive. The proto- 
plasm firmly granular. 

Several minute grains, 
having a rapid vibra- 
tory motion. 

Never more than one in 
a corpuscle. 

Lighter in color, seldom 
crenated. 



122 



TELE STUDY OF MALARIA 



Place of segmen- 
tation. 

Number of seg- 
ments. 

The crescent phase. 



Cycle of develop- 
ment. 



The Segmenting Body 

Within the red blood- 
corpuscles, as a rule. 
Six to eight. 



Outside the red blood- 
corpuscles, as a rule. 
Ten to fifteen or more. 



Crescents small and 
plump, containing small 
amount of pigment. 
Always present double 
outline. 

Twenty- four hours. 



Crescents long, narrow, 
deeply pigmented. Dou- 
ble outline less com- 
mon. 



Forty-eight hours. 



The following table will serve to distinguish the sexes of 
the gametes : 



Microgametocytes. 
Protoplasm stains very slightly. 
Pigment distributed throughout the 

parasite. 
Reniform, short, and broad. 
Chromatin in several scattered 

masses. 



Macrogametes. 
Protoplasm stains more intensely. 
Pigment collected near center, often 

in a circle. 
Crescentic, longer and narrower. 
Chromatin in one or two large 

masses near the center. 



The chief characteristics of the species of malarial parasites 
may be tabulated as follows : 



Length of asexual 
cycle. 

Site of sporulation. 



Movements. 
Pigment. 



Effect on red cell. 



Size of adult. 



Sporocyte. 

Spores. 

Gametes. 



Tertian. 
48 hours. 



May sporulate in 
peripheral 
blood, chiefly 
in visceral cir- 
culation. 

Active. 

Fine, yellowish 
or dark brown, 
scattered, ac- 
tively motile. 

Enlarged, decol- 
orized, Schiiff- 
ner's dots in 
stained films. 

As large as nor- 
mal red 
puscles. 

Mulberry shape. 



Quartan. 
72 hours. 



Equally in peri- 
pheral and vis- 
ceral blood. 



Sluggish. 

Coarse, dark 
brown or black 
(at periphery), 
slightly motile. 

Normal size or 
smaller, often 
and 



cor- 



12-26, 
16. 
Spherical 



dark 

brassy. 
Smaller than 
normal corpus- 
cles. 
Symmetrical 
daisy shape, 
oftenest 6-12, oftenest 8. 

Spherical. 



Estivo-autumnal. 

24 hours, 48 
hours, or ir- 
regular. 

Visceral circula- 
tion. 



Active. 
Scanty, fine. 



Often shrunken, 
may be dark 
and brassy. 

Much smaller 
than normal 
corpuscles. 

Irregular. 

5-30. 
Crescentic. 



It is not infrequently difficult to differentiate young tertian 
from young estivo-autumnal rings, though the following table, 



ETIOLOGY 123 

adapted from Ewing, 130 will enable a comparison of the main 
features : 

Tertian. Estivo-autumnal. 

Nucleus achromatic to methylene- Nucleus stains intensely with methy- 

blue. lene-blue. 

Ring usually coarse and irregular. Ring geometrically circular, deli- 
cate, usually a typical signet-like 
swelling. 
One or two grains of pigment al- Pigment almost constantly absent. 

most invariably present. 
Ring usually pigmented before Chromatin always subdivides before 

chromatin subdivides. pigment appears. 

Infected cell swollen. Infected cell shrunken. 

The Sporogonic Cycle. — If the anopheline mosquito ob- 
tains blood containing only schizonts, the latter soon perish in 
the digestive canal of the insect. However, if the blood con- 
tains mature gametes of both sexes these undergo the exogen- 
ous cycle, to be prepared to reinfect man bitten by the infected 
mosquito. The portion of the mosquito in which this trans- 
formation takes place is the stomach or midgut. Shortly after 
the infested blood has been sucked into the stomach the micro- 
gametocytes exflagellate, the microgametes become free, and 
the macrogametes emit small protuberances to receive the fla- 
gella or spermatozoa. The latter forces an entrance into the 
macrogamete at the site of the protuberance, and the resulting 
fertilized body is known as the zygote. All this has taken place 
within the first few hours. In its early stages the zygote re- 
sembles the ovoid body, but is larger. It is pigmented, it en- 
larges, becomes pyriform, and has the power of locomotion. 
The zygote burrows through the epithelial coat of the midgut 
to the tunica elasticomuscularis, becomes spherical and en- 
cysted, and is known as the oocyst. It enlarges so that it 
projects like a spherical excrescence into the body cavity or 
blood sinus, where it is nourished. The stomach of a badly- 
infected mosquito may be studded with these outgrowths. The 
oocyst attains a size of 40 to 70 microns in diameter. Its 
nuclear chromatin divides and subdivides, each portion sur- 
rounded by protoplasm, polygonal or irregular in shape from 
pressure, being known as the sporoblast. Each sporoblast 
splits into a large number of sporozoits, each enclosing a bit 
of chromatin. The sporozoits remain attached by one end to 



124 THE STUDY OF MALARIA 

the residual body of the sporoblast until the oocyst bursts, when 
the sporozoits escape into the body cavity. Finally, through 
the lacunar circulation, they arrive at the salivary glands, 
where they congregate in hordes. The sporozoits number 
from a few hundreds to ten thousand or more, each measures 
about 14 microns in length, about eight times as long as broad, 
being very slender, tapering at both ends, and endowed with 
serpentine movements. From the salivary glands the sporo- 
zoits are injected by the mosquito, in the act of preying upon 
its victims, where each sporozoit soon enters a red cell and goes 
through the schizogonic cycle. The duration of the mosquito 
cycle varies from eight to sixteen or more days, depending 
mainly upon the temperature, but possibly also upon other 
factors. 

The three species of parasites are closely similiar in their 
stages of exogenous development. The differences between 
the tertian and the estivo-autumnal organisms are that in the 
former the zygote is round or oval instead of pyriform. or 
ovoid, the protoplasm is less refractive, the characteristic pig- 
ment maintains, the sporoblasts are larger and less numerous, 
the sporozoits are less dense and more regularly arranged, 
often radially within the sporoblast, and black spores have not 
been found. 

The quartan parasite is the most difficult to develop within 
the mosquito. 

The Parthenogenetic Cycle. — Parthenogenesis, or virgin 
birth, is reproduction by unfertilized females. 

This phenomenon, known also as the "alternation of genera- 
tions," has been most carefully studied in plant lice, the 
Aphides. The eggs, which are laid in the fall and have hiber- 
nated, hatch in the spring into females, having the power of 
giving birth, without fertilization, to viviparous young, which 
inherit the faculty of parthenogenesis, and procreate in this 
manner until the advent of cold weather or the failure of 
nourishment when males and oviparous females are brought 
forth. From these latter, after copulation, ova are produced, 
and the cycle recommences. 

Parthenogenetic reproduction is known to occur in a number 



ETIOLOGY 125 

of species, as hemoproteus, certain rotifera, jelly-fish, worms, 
entomostracea, acarina, and certain insects, the silk-moth, mos- 
quitoes, gall-flies, ants, bees, wasps, chironomus, etc. 

This life cycle of the parasite of malaria is the most recently 
recognized and least known of its cycles. Since the discovery 
of the parasite the gametes have been regarded as closely 
allied with the chronic malaria and relapses. Golgi plainly 
stated it as his belief that the crescent was the parasite of 
fevers recurring at long intervals. 

Canalis, 131 in 1889, described and pictured spherical bodies 
derived from crescents in the act of sporulation. In 1890 
Antolisei and Angelini 132 confirmed the observation of Canalis. 
Lewkowicz 132 reported, in 1897, tnat ne na d seen sporulating 
crescents some of which contained as many as thirty spores. 

Grassi 133 expressed the opinion in 1901 that the parasites of 
malaria underwent a parthenogenetic cycle of development 
whereby the species was perpetuated after the death of the 
schizonts. 

He cited a number of arguments in support of the theory, 
and referred to a similar process in other protozoa, Adelea, 
Trichosphccrium, and Volvox. 

It was Schaudinn 13 * who, in 1902, first observed and cor- 
rectly interpreted parthenogenesis of tertian macrogametes. 
The case in which this was observed was that of Frau Kossel, 
who, during the spring and summer of several preceding years, 
had suffered occasional paroxysms. On April 29 and May 1 
two severe paroxysms occurred. At the height of the fever 
on May 1 the blood was examined and tertian parasites found 
in abundance; besides schizonts, male and female gametes 
were numerous, showing that it was a typical relapse. During 
May the blood was examined regularly and found to contain 
tertian gametes in greater or less numbers. On May 25, at 
noon, the blood examination showed no marked variation 
from the usual findings, except that the parasites were some- 
what more plentiful. In every preparation were 10-20 macro- 
gametes and occasional microgametocytes. The temperature 
was normal. On the morning of May 26 a remarkable condi- 
tion of the macrogametes, with noteworthy nuclear changes, 



126 THE STUDY OF MALARIA 

described below, were detected. The blood was examined 
every two hours, and the temperature was taken with the fol- 
lowing results : 

A. M. Centigrade - 

10.00 37.8 

P. M. 

12.15 38.4 

2.00 37.5 

5-15 374 

9-15 37-0 

At 12.15 and at 2 p. m. parthenogenetic forms were most 
abundant. In the evening, besides unchanged sexual organ- 
isms, very young endoglobular schizonts were found. 

On May 27 the blood was examined twice; at 7 a. m. only 
young endoglobular schizonts were found, the temperature 
36.8 ; at 8 p. m. only scanty, half-grown schizonts were found, 
and the temperature was yj. 

On May 28 the typical attack (depending on asexual sporu- 
lation) occurred, with the following temperature course: 

A. M. Centigrade. 
7.00 37-6o 

10.00 39.00 

P. M. 

12.15 39-85 

I.I5 40.75 

2.15 40-40 

3-30 39-10 

5-15 39-00 

7.00 37-8o 

9-15 37-45 

May 29. 

A. M. 

7.00 36.40 

The result of the blood examination was as usual in such 
attacks. 

The next morning most of the young parasites were found 
to be gametes. Thus a true alternation of generations. It 
should be observed that, while the sporulation of the unfer- 
tilized macrogametes or parthenogametes (if it is permissible 
to coin a much-needed term) caused a slight rise of tempera- 
ture, it did not compare to the height reached during schizo- 
gonic sporulation. It is indeed highly probable that sporula- 
tion of a small number of parthenogametes might occur with- 





Fig. 48. — Parthenogenesis of the tertian parasite (after Schaudinn). 



ETIOLOGY 127 

out perceptible rise of temperature, and that the paroxysm 
would ensue only when sporulation of schizonts occurred in 
sufficient numbers. 

Schaudinn 134 thus describes the process of parthenogenesis 
as he observed it in tertian malaria (Fig. 48). The chromatin 
of the parthenogamete collects in coarse fragments and cords 
toward one end of the bean-shaped nucleus, and stains in- 
tensely, while the other somewhat larger half contains fewer 
and smaller chromatin particles and stains faintly. The nucleus 
then divides into two, one containing the coarse, deeply staining 
chromatin, and the other the fine, diffusely staining chromatin, 
the former resembling the nucleus of a schizont before nuclear 
proliferation. A constriction may be perceptible about the 
parasite almost separating a deeply staining, highly pigmented 
portion containing the pale-staining nucleus from a lightly 
stained and less pigmented portion 'v T hich lies the deeper 
stained nucleus. This nucleus now si s, and the portion 

of the plasma in which it lies proceed .0 sporulation in a 
manner similar to schizogonic sporulation, the spores becom- 
ing typical schizonts. 

Maurer, 135 in 1902, observed sporulation of estivo-autumnal 
gametes, and construed it as parthenogenesis. 

Ziemann 48 believes that he has seen parthenogenetic repro- 
duction of quartan gametes. 

Bluml and Metz 136 observed sporulating parthenogametes in 
six preparations taken from 5 patients with tertian malaria. 
The process was identical with that described by Schaudinn. 
Young and sporulating schizonts and young gametes were 
present in these same preparations. 

Are the parthenogametes identical with true macrogametes 
which do not proceed to sporulation ? Such a doubt is hardly 
justifiable from a review of the scientific studies of the learned 
Schaudinn and of the other observers cited above. Craig, 137 
however, has recently adduced evidence that latency and re- 
lapses are dependent upon resting bodies, the products of intra- 
corpuscular conjugation of young schizonts. He does not, 
however, follow these forms further than the completion of 
conjugation, and while it is possible that this is the origin of 



128 



THE STUDY OF MALARIA 



the parthenogametes, there is as yet no positive evidence that 
the latter are not true macrogametes. 

Inasmuch as different terms are employed by various authors 
to describe the morphology of the malarial parasite, to the 
great confusion of the student, the writer has prepared a brief 
glossary of these terms. The definitions must not be taken 
in the wide zoologic sense, but only as applied by the majority 
of writers to the parasite of malaria : 



Amphigony. See Sporogony. 

Amphiont. See Zygote. 

Androspore. See Microgamete. 

Antheridium. See Microgametocyte. 

Asexual Cycle, the schizogonic or 
human cycle of parasitic repro- 
duction. 

Blast. See Sporozoit. 

Blastophore. See Sporoblast. 

Copula. See Zygote. 

Crescent, one form of the estivo- 
autumnal gamete. 

Definitive Sporoblast. See Zygote. 

Endogenous Cycle. See Schizogony. 

Enhemospore. See Merozoite. 

Exogenous Cycle. See Sporogony. 

Exotospore. See Sporozoit. 

Flagella, microgametes. 

Gamete, sexual form of the parasite. 

Gametoblast. See Sporozoit. 

Gametocyte, cell giving origin to 
gametes. 

Gametospore. See Zygote. 

Germinal Rod. See Sporozoit. 

Gymnospore, a schizogonic spore or 
merozoit. 

Gynospore. See Macrogamete. 

Hcemosporidia, the suborder of pro- 
tozoa to which the malarial para- 
site belongs. 

Human Cycle, the schizogonic or 
endogenous cycle. 

Macrogamete, a female gamete. 

Macrogametocyte, a female gameto- 
cyte. 

Macrospore. See Macrogamete. 

Merozoite, a spore the product of 
schizogony ; also applied to the 
sporozoit after it has entered the 
red cell. 

Microgamete, a male gamete, flagel- 
lum, spermatozoan. 

Microgametocyte , a male gameto- 
cyte. 

Microspore. See Microgametocvte. 

Monogony. See Schizogony. 

Mcnont. See Schizont. 

Mosquito Cycle, the sexual or sporo- 
gonic cycle. 



Nomospore. See Merozoit. 

Ondeterospore. See Schizont. 

Oocyst, an encysted zygote. 

Ookinete. See Zygote. 

Ovoid, one form of the estivo- 
autumnal gamete. 

Parthenogamete (new word), an 
unfertilized sporulating macro- 
gamete. 

Parthenogenesis, virginal reproduc- 
tion. 

Polymitus, an exflagellated micro- 
gametocyte. 

Reproductive Cycle, the sporogonic 
or mosquito cycle. 

Schizont, the asexual form of the 
parasite. 

Schizogony, the asexual, human or 
endogenous cycle of development. 

Sexual Cycle, the sporogonic, mos- 
quito or exogenous cycle. 

Sperm-mo there ell. See Microgame- 
tocyte. 

Spore-cyst. See Oocyst. 

Spore-mothercell. See Sporoblast. 

Sporoblast, spherical or polygonal 
bodies contained in the oocyst, 
giving origin to the sporozoits. 

Sporocyte, a sporulating schizont. 

Sporogony, the sexual cycle of de- 
velopment. 

Sporont. See Oocyst. 

Sporozoa, the class of protozoa to 
which the malarial parasite be- 
longs. 

Sporozoit, a spore the product of 
sporogony. 

Syzygies, the products of conju- 
gating parasites. 

Trophic Cycle, the asexual cycle. 

Trophozoit, a young intracellular 
parasite of asexual origin ; a 
merozoit which has entered the 
red cell. 

V ermicule. See Zygote. 

Zooid. See Sporozoit. 

Zygote, a fertilized macrogamete. 

Zygotoblast. See Sporozoit. 

Zygotomere. See Sporoblast. 



ETIOLOGY 129 

Cultivation Experiments. — Coronado 138 claimed to have 
been successful in cultivating the malarial parasites from water 
which he believed infected. He stated that the entire cycle 
could be followed. Miller 86 also believed that he had cultivated 
the organisms. These experiments have been repeated, but the 
results could not be confirmed, hence were probably incorrect. 

Sakharov, Rosenbach, Blumer, Hamburger and Mitchel 139 
succeeded in maintaining the organisms alive for several days 
in the bodies of leeches which had sucked the blood from 
malarial patients. Hamburger's experiment is thus described 
by Thayer: 98 "Mr. Hamburger took the blood from a case of 
estivo-autumnal fever with quotidian paroxysms at a time when 
only small ameboid and ring-shaped, non-pigmented hyaline 
bodies were present. During the next several days he was 
able to distinguish a slight increase in size with the accumula- 
tion in nearly every organism of a few small motile pigment 
granules. On the eighth day the organisms were distinctly 
visible, each with a small group of slightly motile granules 
in the middle or at some point on the periphery of the parasite. 
The parasites, as in Dr. Blumer's case, showed no actual 
ameboid movement, though some slight change of shape could 
at times be made out. In both instances the parasites acquired 
after several days a peculiar refractive, glistening appearance. 
Specimens stained on the eighth day showed characteristic 
ring-shaped bodies." 

PATHOGENESIS 

Much fanciful speculation has been indulged in as to the 
cause of the paroxysms until Golgi and others of the Italian 
school showed that it was closely connected with the life history 
of the malarial parasites (Fig. 49). 

The paroxysm is not immediately associated with the gradual 
vegetative growth of the parasite within the corpuscle, but, 
occurring more or less abruptly as it does, is simultaneous with 
sporulation and the sudden discharge into the blood stream of 
a new generation of parasites. In what manner does this 
process produce so peculiar a phenomenon as the malarial 
paroxysm? Golgi 87 was of the opinion that it was dependent 
9 



13° 



THE STUDY OF MALARIA 



upon the entrance into fresh red cells of the young generation 
of parasites. This, however, is shown to be erroneous by the 
fact that a properly timed and adequate dose of quinine given 
before the chill is expected does not prevent the access though 
it does destroy the young parasites, preventing their invasion 
of the cells. 

The true explanation of the origin of the paroxysm is 
through the agency of a toxin liberated by the sporulative act. 
The existence of a toxin, the product of the malarial parasite, 




cm 

QqqU 



o © 



Fig. 49. — The relation between the stages of the parasite and the paroxysm. 

is almost universally assumed by students of malaria. The 
grounds for this assumption may be recounted as follows : 

1. An analogy with other infectious diseases. 

2. Immunity ; this immunity is not absolute, but that a rela- 
tive immunity to malaria exists there is no room for doubt. 

3. The formation of an antitoxin; Ford's 140 experiments 
being conclusive as to the existence of such. 

4. Degenerative changes in the kidneys, liver, spleen, and 
other organs not otherwise explainable. 

5. Blood changes, as anemia out of proportion to the num- 



ETIOLOGY 131 

ber of parasites, and brassy degeneration, stippling, and poly- 
chromatophilia of the red cells. 

6. Increased toxicity of the urine and sweat. 

7. The existence of coma in malaria without parasites or 
pigment in the brain. 

8. The fever and its relation to parasitic sporulation. 

9. Experimental proof. The negative results of Gualdi, 79 
Montesano, 79 Mannaberg, 14 ^ and Celli 80 are devoid of weight 
against the convincing experiments of Rosenau, Parker, Fran- 
cis and Beyer, 142 who demonstrated the existence in malarial 
blood of a poison capable of reproducing the symptoms of 
the disease when injected into the veins of other men. The 
details of their experiment with tertian malaria are reproduced 
as follows: 

"Andrez Mendez (Case LXVI), 39 years old; born in La 
Luz, Estado de Guanajuato ; never had fever in his native place. 
In 1878 had yellow fever ( ?) in San Antonio, Estado de 
Guanajuato, with which he says he was sick about one month. 
He came to Vera Cruz three years ago, and has had fevers 
five or six times since. Present illness dates from about 
November 3, but states that he had been troubled with mild 
attacks of fever for a month, which he describes as coming 
on alternate days, but not sufficiently severe to keep him from 
his work. 

"The fever which initiated his present sickness began with a 
severe chill and was followed by fever and sweat, and was 
associated with some nausea and vomiting. He states that 
these paroxysms were repeated daily until his admission to 
San Sebastian Hospital, November 6, 1903. 

"Blood examination showed that he had a heavy infection 
with tertian parasites, and he was immediately transferred to 
the laboratory of Working Party No. 2, Yellow Fever Insti- 
tute. 

"The man was physically robust, but very anemic, mucous 
membranes particularly pale, skin cold and damp. 

"At about noon on this date (November 6) the patient was 
seized with a chill. 

"By 12.30, half an hour later, the rigor was very marked ; he 



132 THE STUDY OF MALARIA 

lay in bed with a blanket drawn over his head, and was shak- 
ing violently; he could not hold a thermometer in his mouth 
and the pulse was taken with difficulty. During this time the 
temperature was rapidly rising, it being now 39.1° C. 

"At 12.40 blood was drawn from one of the superficial veins 
at the bend of the elbow. On account of the rigor there was 
some difficulty in introducing the needle. The blood flowed 
freely; 125 cc. were quickly drawn. It was permitted to flow 
into a porcelain dish and immediately defibrinated by whipping 
with sterilized forks. Clotting took place very quickly, so 
that the fibrin was readily and quickly separated from the fluid. 

"Judging from the size of the clot and color, the fibrin had 
enmeshed a number of corpuscles. The defibrinated fluid 
showed no further tendency to clot, and on microscopical 
examination looked like fresh blood containing a normal num- 
ber of corpuscles. 

"To 25 cc. of defibrinated blood was added 25 cc. of physio- 
logical salt solution, and this diluted blood was filtered through 
the same Berkefield filter in the same manner as was done 
with the blood of Filomena Martinez. This filter when tested 
later, March 1, 1904, held back Staphylococcus pyogenes 
aureus. 

"Nine cc. of the filtrate were injected into the right basilic 
vein of Louis Peredo as soon as this amount could be obtained. 
This injection took place at 1.40 p. m. It only took about 
forty minutes to defibrinate and filter the blood, which process 
was done as rapidly as possible. 

"Stained smears of the filtrate showed no morphologic ele- 
ments. The filtrate had a distinct red color. 

"As a control, Jose Ojeira, at 2 p. m., was given an injection 
into his left basilic vein of 4 cc. of the unfiltered mixture. As 
the blood was diluted with equal parts of salt solution, he, 
therefore, received 2 cc. of Mendez's blood. 

"The unfiltered mixture of defibrinated blood and salt solu- 
tion, upon microscopic examination shortly after Ojeira re- 
ceived his injection, showed ameboid tertian organisms with 
dancing pigment. 

"After drawing the blood from Mendez he continued to have 



ETIOLOGY 133 

a chill, with a severe rigor and chattering of the teeth, accom- 
panied by nausea and vomiting. His temperature continued 
to rise after the blood was drawn until it reached 40.2° C. 
The febrile period was followed by drowsiness and moisture 
of the skin. 

"As will be seen by reference to the temperature chart, Men- 
dez was kept under observation without quinine, and had 
another typical malarial paroxysm the next day. All the evi- 
dence in his peripheral blood, which was examined frequently, 
pointed to a severe double infection with the tertian parasite. 

"He was then given quinine, which entirely controlled the 
disease and caused the complete disappearance of the parasite 
from his peripheral blood. 

"The results caused by the injection of the blood of Andres 
Mendez into Peredo and Ojeira follow : 

"Luis Peredo (Case LXIV), a volunteer, aged 25; born in 
Jalapa, State of Vera Cruz, where he has always lived. When 
examined at Jalapa, August 26, he was found to be physically 
sound; urine contained no albumin; peripheral blood showed 
no plasmodium. 

"He was brought to Vera Cruz August 28 and taken from 
the station directly to the laboratory, from which time he was 
kept constantly within a mosquito-proof room. 

"On October 27, after having been under daily observation 
two months, during which time he remained in normal health, 
he was injected with the filtered blood of Filomena Martinez, 
who at the time was suffering with a paroxysm of malarial 
fever of the estivo-autumnal type, his blood containing many 
young ring-forms and crescents. 

"It will be noted by reference to the records of Filomena 
Martinez that the blood was drawn during the time of the 
decline of the paroxysm. It was then allowed to clot in the 
ice chest, the clear serum was pipetted off and diluted with 
an equal quantity of isotonic salt solution, and this filtered 
through a new Berkefield filter. 

"Twenty cc. of the filtrate, which on account of the dilution 
represented 10 cc. of the blood serum, were injected into the 
left median basilic vein of Peredo. 



134 THE STUDY OF MALARIA 

"For further details of the manner in which the blood serum 
was obtained and the nitration performed, see the above 
records of Filomena Martinez. 

"Peredo was carefully watched from the hour he was in- 
jected, but he remained in good health, and no deviation from 
the normal was detected. 

"His temperature was taken every four hours during the 
night and day, both before and following the injection, as 
will be seen by the temperature chart. No symptoms devel- 
oped. 

"His blood was examined daily for plasmodium, but none 
was found. The result of this injection must, therefore, be 
considered negative. 

"Ten days later he was again injected with filtered malarial 
blood under different circumstances, and with positive results. 

"At 1.40 p. m., November 6, he was given an intravenous 
injection of the blood of Andres Mendez, passed through the 
same Berkefield filter as before. Mendez was suffering with 
a double tertian infection; his blood was drawn during his 
chill and before the height of the paroxysm, as will be seen 
by reference to the temperature chart. 

"Thinking that allowing the blood to clot four or five hours 
in the ice chest in order to obtain a clear serum for filtration 
might be too severe a tax upon the vitality of the malarial 
parasite, we this time defibrinated the blood as quickly as 
possible, diluted it as before with an equal volume of physio- 
logic salt solution, and filtered it through the same Berke- 
field filter in the same manner as was done with blood of 
Filomena Martinez. 

"As soon as 9 cc. of the filtrate could be obtained it was in- 
jected into the basilic vein of the right arm of Louis Peredo. 
This injection took place at 1.40 p. m. 

"About thirty-five minutes after receiving the injection he 
began having chilly sensations and headaches, and presently 
went to bed, covering himself with his blanket (2.25 p. m.). 
Five minutes later he was having a violent chill, his teeth chat- 
tering so that we could not trust the thermometer in his mouth. 
The rigor of the entire body was so marked that there was 



ETIOLOGY 135 

difficulty in taking the radial pulse. The face was pale, and 
at this time he vomited most of the dinner he had eaten a 
short time before receiving the injection. 

"The patient complained of headache, which he localized at 
the forehead and occiput; says he felt cold and had pains in 
the knees. At this time the skin was dry. The chill lasted 
somewhat over half an hour. 

"At 3 p. m. the patient had transient chilly creeps, very 
slight rigor. 

"At 3.15 p. m. he said he felt 'warm inside,' and all sense 
of chilliness had disappeared ; still his headache. 

"At 3.25 p. m. he complained of marked pain in his legs. 

"At 3.30 p. m. he vomited the remainder of his dinner. 

"It will be seen from the temperature chart that during this 
time his temperature was rapidly rising, and reached its high- 
est point (38.7° C.) at 4 p. m., just two hours and twenty 
minutes after receiving the injection. 

"The pains in the knees and back continued, and nausea and 
vomiting now became a distressing feature of the paroxysms 
for the patient. 

"The fever gradually subsided, and reached normal at 4.30 
A. m. the next morning. 

"As the fever subsided the skin became moist, the nausea 
and pains gradually disappeared, so that by 6 p. m. the patient 
was quiet and dozing. The entire paroxysm, therefore, ac- 
cording to the temperature record, lasted about eight hours, 
although the patient was sleeping quietly five hours after 
receiving the injection. 

"It is interesting to note that this man (Pedro) had what 
seemed to be a typical malarial paroxysm, beginning with a 
distinct rigor associated with a rise of temperature and fol- 
lowed by slight sweating. It is of particular interest to note 
that his paroxysm, so far as symptoms were concerned, was 
very much like the paroxysm from which Andres Mendez 
suffered, especially the nausea and vomiting. 

"Pedro was kept under very close scrutiny until November 
24, eighteen days following the injection, during which time 
he remained entirely normal and no plasmodium appeared in 



136 THE STUDY OF MALARIA 

his peripheral blood, which was frequently examined, as fol- 
lows: 

"November '6 — 4.30 p. m., 8 p. m. No malaria. 
"November 7 — 4.30 a. m., 8.30 a. m., 12.30 p. m., 5 p. m., 

1 1 p. m. No malaria. 
"November 8 — 7 a. m., i p. m., 6 p. m., 9.30 p. m. No malaria. 
"November 9 — 7.30 a. m., 1.30 p. m. No malaria. 
"November 10 — 2 a. m., 3.30 p. m., 8 p. m., five minutes each. 

No malaria. 
"November 11 — 4, 7, 10 a. m., 2, 6, 11 p. m., five minutes 

each. No malaria. 
"November 12 — 1.30,6.25 a.m., five minutes each. No malaria. 
"November 13 — 7 a. m., 9.30 p. m., five minutes each. No 

malaria. 
"November 14 — 8 a.m., 8 p.m., five minutes each. No malaria. 
"November 15 — 8 a. m., 8.30 p. m., five minutes each. No 

malaria. 
"November 16 — 7 a. m., 9.30 p. m., five minutes each. No 

malaria. 
"November 17 — 8 a. m., 8 p.m., five minutes each. No malaria. 

"Jose Ojeira (Case XXIII), a volunteer from Jalapa, 18 
years old; he had never lived on the coast, and says that he 
never had fever of any kind. On examination in Jalapa, 
August 11, he was found to be physically sound, of robust 
physique; urine showed no albumin, and blood examination 
for malaria was negative. 

"He was taken to Vera Cruz August 13 and immediately 
transferred to a mosquito-proof room in the laboratory, where 
he was kept under close observation. 

"On August 28, at 9.30 a. m., he was bitten by four mosqui- 
toes, two of which had bitten Antonio Leal (Case XXXV), 
a yellow-fever patient, fifteen days seventeen hours previously, 
and the other two had bitten the same case fourteen days 
twenty-three hours previously. 

"The man was kept under close observation in a mosquito- 
proof room, but showed no reaction. There was no rise of 
temperature, nor did he present any untoward symptoms. 

"On October 27, 7 p. m., he received intravenously 20 cc. of 



ETIOLOGY 137 

diluted blood serum of Filomena Martinez (estivo-autumnal 
infection), passed through a Pasteur-Chamberland filter B. 
This represented 10 cc. of blood serum. For details of this 
filtration see Filomena Martinez. 

"Ojeira showed no reaction whatever as a result of this 
injection. 

"It will be noted that the blood of Martinez was drawn after 
the height of the paroxysm and while the temperature was on 
the decline. 

"Martinez was suffering with a very severe estivo-autumnal 
infection at the time the blood was taken. 

"Ojeira's blood was examined several times daily, both before 
and following this experiment, and at no time was anything 
resembling a malarial parasite seen in his peripheral blood. 

"On November 6, the patient having continued in good 
health since the last experiment was used as a control for the 
experiment made on Peredo. 

"On this date, at 2 p. m., he was given an intravenous injec- 
tion of 4 cc. of the unfiltered, diluted, and defibrinated blood of 
Andres Mendez. At the time the blood was drawn from 
Mendez it contained a heavy infection of double tertian mala- 
ria, and the blood was taken from him during a chill and before 
the height of his paroxysm. It was at once defibrinated, diluted 
with an equal volume of physiologic salt solution and filtered 
through a Berkefeld filter. Nine cc. of the filtrate were given 
intravenously to Peredo, causing a malarial paroxysm without, 
however, the presence of the malarial parasite, and due, as 
we believe, to the toxin (?) in the blood of Mendez. 

"Ojeira, who received 2 cc. of unfiltered blood (4 cc. dilu- 
tion), reacted within an hour, with a slight rise of temperature 
and nausea, and four days following developed a typical mala- 
rial paroxysm, with many tertian parasites in the peripheral 
blood. 

"There can be no doubt that the reaction to the 2 cc. of 
defibrinated blood injected into the vein of Ojeira caused a 
slight paroxysm, which it is reasonable to suppose was due 
to the same poison present in the blood of Mendez, and which 
also caused the reaction in Peredo. 



138 THE STUDY OF MALARIA 

"It will be noticed that 2 cc. of this blood caused but a 
slight reaction in the case of Ojeira, while 4.5 cc. caused a 
more marked reaction, with a rise of temperature to 38.7° C. 
in the case of Peredo, indicating in a very definite manner that 
the severity of the symptoms were directly due to the quantity 
of poison introduced. Ojeira did not have a chill or other 
manifestations of a malarial paroxysm other than a rise of 
temperature and nausea. He vomited gastric mucus several 
times. 

"On November 10, the fourth day following the injection, 
Ojeira had a typical malarial paroxysm, with tertian parasites 
in his peripheral blood. He suffered with a double infection, 
having a chill every day, as will be noticed by reference to 
the temperature chart. 

"The character of the parasites in his blood and the clinical 
course of the disease resembled in all respects those of Mendez, 
from whom the blood was taken. Both cases were entirely 
controlled by quinine." 

The parasites of tertian and quartan infections develop 
uniformly, one generation at a time, hence typical paroxysms 
are the rule. Sometimes, it is true, sporulating forms are met 
with between the accesses, but a certain dose of toxin is neces- 
sary to excite a fit. The estivo-autumnal parasites, on the 
other hand, do not sporulate so uniformly, hence the poison is 
liberated in broken doses and typical paroxysms are more fre- 
quently lacking and the fever more continuous or irregular. 
If sporulation occurred more nearly simultaneously, as in the 
tertian and quartan forms of malaria, it is probable that the 
sudden discharge of the more highly poisonous estivo-autumnal 
toxin would be more often attended with serious consequences. 
The uniform sporulation of the tertian and quartan parasites 
may be likened to a body of soldiers firing by volleys, while 
that of the estivo-autumnal parasites is similar to soldiers 
firing at will. 

The change of type of malarial attacks has been used as 
an argument for the unity of the malarial parasites. It is 
well known, however, that such occurrences are best explained 
by a number of different species. Quotidian malarial parox- 



ETIOLOGY 139 

ysms due to two generations of tertian organisms may become 
tertian in character by the destruction of one generation. 
Quotidian paroxysms due to a triple quartan infection may 
become quartan or double quartan by the death of two genera- 
tions or of a single generation of parasites. On the contrary, 
tertian and quartan accesses may become quotidian by the 
development into activity of one or two additional generations. 

It is remarkable in multiple infections by different genera- 
tions of the same species of parasite that they almost always 
sporulate on different days and very often about the same 
time each day. Thus it is very rare in double tertian infec- 
tions that two paroxysms should occur within one day followed 
by a fever-free day. This is probably best explained by the 
mode of infection. It is known that the malarial mosquitoes 
feed almost solely at night and usualfy only once during the 
night. If a subject is inoculated by the mosquito on two suc- 
cessive nights it is obvious that the parasite would become 
mature with an interval of about twenty-four hours between 
the generations. If inoculation should occur upon three or 
more successive nights it is probable that the third and succeed- 
ing generations would sporulate, after incubation, simul- 
taneously with the first and second. The interval between 
multiple quartan infections may be explained similarly. 

Latency and relapses were formerly explained upon the 
theory that so long as the parasites remained below a certain 
level of asexual reproduction the disease was latent, and when 
the parasites exceeded in number this level a relapse occurred. 
Sims has estimated the greatest number of adult parasites 
which the body can endure without symptoms as about two * 
billions. It is probable that brief periods of latency may be 
thus explained, especially in persons possessing a relative im- 
munity, but it is evident that this is not a common mode, par- 
ticularly of relapses at long intervals, since the asexual cycle 
is known to wear out spontaneously after certain periods. 
These relapses at long intervals can be explained by partheno- 
genesis alone. After the schizonts have perished, while the 
microgametocytes do not persist long, the macrogametes re- 
main for indefinite periods. They may sporulate more or less 



140 THE STUDY OF MALARIA 

regularly, causing paroxysms at intervals of about a week, or 
multiples thereof, or may lie dormant until aroused into repro- 
ductive activity by exposure or dietary or other excesses. It 
is highly probable that the parthenogenetic cycle of reproduc- 
tion is conducted almost altogether in the visceral circulation, 
particularly in the spleen. As evidence of this may be cited 
the outbreaks of malaria following cold douching, electrical 
stimulation, and trauma of the splenic region. 

The anemia of malaria depends upon three factors: i, the 
mechanical destruction of cells by the parasites ; 2, the effect 
of toxins, and, 3, the activity of the blood-making organs. 
Liberated hemoglobin is transformed by the liver into bile 
pigment. When the hemoglobin is liberated too fast for the 
liver to utilize, hemoglobinemia results, and hemosiderin is 
precipitated from the blood. The increased activity of the 
liver results in polycholia and icterus. It is probable that jaun- 
dice is due also when the liver capacity is overtaxed to hemo- 
globinemia. When hemoglobinemia exceeds a certain limit the 
hemoglobin is excreted by the kidneys, resulting in hemo- 
globinuria. 

Splenic enlargement is effected through hyperemia, deposi- 
tion of detritus of destroyed erythrocytes, accumulation of 
parasites, and hyperplasia of the pulp. 

Spontaneous cure is probably due to the natural weakening 
of the reproductive powers of the parasite, a phenomenon 
occurring in strains throughout the vegetable and animal king- 
doms, and possibly also to the influence of an antitoxin. 
Phagocytosis plays, in the opinion of the writer, a much less 
prominent role than is usually attributed to it. It is probable 
that this function is exercised mainly after the parasites have 
lost vitality from other causes. 

ETIOLOGY OF PERNICIOUS MALARIA 

Pernicious malaria is that form of malaria so acute that, 
independently of complications, life is endangered in a few 
hours or a few days. This gravity may be due to the intensi- 
fication of ordinary malarial symptoms or to the advent of 
unusual ones. It should be clearly understood that pernicious 



ETIOLOGY 141 

fever is not a pathologic entity, but is a form of malaria, 
from the simple modes of which it sometimes differs only in 
degree. 

In America pernicious malaria is rarely seen in the adult 
negro, by far the greater number of cases occurring in this 
race being in children under ten. This coincides with the expe- 
rience of those who have practised among the blacks of Africa. 
It is not common among the natives of Algeria or Arabia. 
The natives of India are not immune, and the Chinese are 
very susceptible. Koch 143 relates that of 273 Chinese imported 
from Hong Kong to Stephansort in 1898, 125 died within the 
course of a year, mostly of malaria. 

More cases occur in males than in females. This is not 
because of greater susceptibility, but on account of more fre- 
quent exposure of the male sex. Crespin 144 believes that preg- 
nancy may render pernicious attacks that have no grave tenden- 
cies. Bell 145 reports a case of comatose malaria in a Chinese 
woman who was eight months pregnant. Premature delivery 
occurred on the second day, the child being dead, and the 
mother died on the seventh day. Dos Santos 146 describes a 
case of algid malaria in a woman, age twenty-seven, six months 
pregnant. Abortion occurred thirty-six hours after onset of 
the attack. The placenta was enormous. The woman recov- 
ered. Ten months later the same woman was assailed with a 
similar attack while six months pregnant. She aborted again 
and made a good recovery. 

Children are prone to pernicious attacks, especially of the 
cerebral type. Sixty-nine cases observed by Martirano 147 give 
the following age distribution: 

Under nine months 6 

One year old 19 

Two years old 12 

From three to four years 8 

From five to ten years 5 

From ten to thirty years 5 

From thirty to seventy years 14 

"69" 

In another series of 25 under Martirano's 147 care, 13 were 
children and 12 were adults. In 31 cases of Tanzarella, 84 19 



142 THE STUDY OF MALARIA 

were under ten years of age and 12 older. Caccini's 147 99 
cases show an unusually small per cent, in children, only 14 
cases occurring in children under ten years of age. 

The convulsive form is relatively frequent in children living 
in highly malarial countries. . According to Thornhill, 148 in 
Ceylon during 1896, 40.52 per cent, of children dying under 
one year of age died of convulsions, most of which were due 
to malaria. Speaking of pernicious malaria in British Malaya, 
Travers says : "The infant mortality on some estates, where 
the coolies suffer much from fever, is terribly high. I know 
of one estate (since abandoned) on which a large Tamil labor 
force was employed where all the infants died. The manager 
offered a reward for the first child successfully reared on the 
estate, but that reward, I believe, was never claimed." 

Convulsive pernicious is apt to attack children with nervous 
predisposition, either hereditary or acquired. It is rare in 
adults, though Maurel, Reynaud, and Duberge have seen such 
cases. 86 The aged are more susceptible to comatose attacks. 

In the Southern States pernicious malaria is more prevalent 
at the height of the malarial seasons, especially in July, August, 
and September. In Southern Europe and in Algiers the season 
is said to be from July to November. In Greece cases appear 
in July are most frequent in autumn, and are rare in winter. 
In India it is at the acme of the malarial season that these 
attacks occur. 

Eleven hundred and one cases from various sources are dis- 
tributed as follows : 

CandeV 49 Marti- Tanza- „•„ „ ,„ r „ • ■ I47 2^ia 
Cochin rano,^ rdla," B & C ^ t T' ™£?L Total - 

China. Italy. Italy. A1 S ena " Italy ' J^ 



I 

1 I 

2 11 



40 

43 

80 

100 

112 

130 



January 39 

February 43 

March 80 

April 99 

May no 

June 126 

July 115 1 8 2 4 S 135 

August 79 5 10 n 18 25 148 

September 54 10 3 13 7 21 108 

October 52 5 2 12 12 7 90 

November 47 4 3 . . 12 6 72 

December 36 . . . . . . 2 5 43 

Total "880 25 31 40 56 69 noi 



ETIOLOGY 143 

The influence of inundations on the etiology of pernicious 
fever is well recognized. In 1826 Johnson 16 wrote : "There is 
no unmixed good in this world. The inundations of the Nile 
and the Ganges, while they scatter fertility over the valley of 
Egypt and the plains of Bengal, sow with a liberal hand at the 
same time the seeds of dreadful diseases." This is in all proba- 
bility true of the Mississippi and other large rivers of our 
country. In 1854 Frerichs recorded an epidemic of pernicious 
malaria following an overflow of the Oder where there had 
previously been only mild cases of malaria. 

The length of residence in a malarial region is probably 
not an important factor in the etiology of the affection. While 
Sims 152 and others believe that it occurs mainly in the early 
period of residence, most of Maurel's 75 cases were in persons 
who had been in the colony a long time. Plehn 5 mentions the 
case of a young physician who died of pernicious malaria six 
days after arrival at Banana. 

Maurel 75 states that outbreaks of pernicious malaria may 
occur several years after return to France from the tropics, 
and without new infection. During and shortly after the war 
with Spain numerous cases which were infected in Cuba and 
the Philippines were treated in American hospitals. Rees 153 
records the case of a man who had spent only five days in an 
endemic region and developed comatose malaria with fatal 
termination in a few weeks after his return to London. Satter- 
lee, 154 Hall, 155 Neer, 156 and others have observed similar cases 
in America. In the majority of such cases the outbreak occurs 
within a few weeks after leaving the endemic area. 

Occupations which subject not only to malarial infection, 
but to hardships and exposure, especially to the sun, predispose 
to pernicious attacks. Manson 59 cites the case of Hong Kong, 
formerly healthy enough, but when barracks and houses were 
being built and roads laid out the soldiers died by the hundred 
of pernicious fevers. Homem 157 asserts that these cases occur 
in Rio de Janeiro, particularly when the sewerage, gas, and 
water companies are making deep and extensive excavations in 
the more central streets of the city. Early in the last century, 
when the marsh of Chartreuse, near Bordeaux, was drained, 



144 THE STUDY OF MALARIA 

an epidemic of severe malaria prevailed, and in 1805 12,000 
people were stricken, of whom 3,000 died in live months. 

As it is especially in the laboring and poorer classes that 
primary infections do not receive adequate treatment, it is 
largely in this class that pernicious attacks are found. 

Pernicious attacks may be first attacks or they may occur 
in cachectics, but it is chiefly between these extremes that most 
attacks originate, namely, in those having had previous attacks 
of malaria, but who are not saturated to the degree of cachexia. 
Laveran, 1 Marchiafava and Bignami, 22 and Sambon 9 have 
never seen pernicious attacks without previous malaria. 
Ruge, 158 however, states that such cases are not uncommon in 
India and both the east and west coasts of Africa. Colin and 
Antoniades have observed like cases. 159 Wurtz and Thiroux 160 
say that the typhoid form is most often a fever of first inva- 
sion. Roux 161 knows of numerous examples of pernicious 
fever as the first manifestation of malaria. Mannaberg 141i 
asserts that it may attack those who have never before suffered 
from malaria, as well as those who have undergone repeated 
attacks. Homem 157 says that in many cases the pernicious 
paroxysm is preceded by simple ones; in others the patient is 
attacked while in perfect health. It is the comatose form that 
is most frequently Seen in those who have not previously been 
attacked with malaria. Crespin's 144 experience is that the at- 
tacks are exceptional in chronic malarials. Smart 76 records it 
that during the Civil War pernicious attacks occurred not only 
in persons who were for the first time exposed to a highly 
malarial atmosphere, but also among those who had suffered 
more or less from the malarial influence before the superven- 
tion of the congestive seizure. In 50 cases observed by Carda- 
matis and Diamessis 35 only one developed as a primary attack 
Most of the algid and comatose cases of Maurel were in sub- 
jects of chronic malaria. Thayer 98 and Craig 70 say that it is 
customary for malarial paroxysms to precede. Schellong 92 
agrees with Martin that pernicious fever attacks persons al- 
ready rendered anemic from malaria. 

While it is probably true that in the majority of instances 
typical paroxysms precede pernicious attacks, it is of the utmost 



ETIOLOGY 145 

importance to bear in mind that the latter may be manifesta- 
tions of first invasion. "If there are cases of pernicious fever, 
in which the patient has been attacked previously by paroxysms 
of simple, well-marked or masked intermittent, there are also 
cases, unhappily numerous, in which it is the pernicious attack 
that opens the scene, where the subject, in the enjoyment of 
the most flourishing health, is treacherously assailed by the 
terrible enemy without the least signal to warn of the enormous 
peril awaiting him." (Homem. ) 

Pernicious malaria is almost as varied in pathogenesis as 
it is in manifestations. Not only are its several forms asso- 
ciated with unlike conditions, but for the explanation of some 
the presence of several different factors is necessary. Thus 
comatose malaria may be associated with at least two different 
forms of the parasite; the peripheral blood may show very 
great numbers of these parasites or they may be scanty ; in the 
brain they may be found in hordes, even to the occlusion of 
small vessels, or they may be entirely absent. 

As may be inferred, no one etiologic element can account 
for all cases, even of the same type. Probably the only essen- 
tially common factor is the presence of the malarial parasite, 
the manifestations of which run the gamut from the mildest 
intermittent to the profoundest cachexia, from the most art- 
fully masked to the deadliest pernicious. 

Until comparatively recently it was believed that infections 
with the so-called benign organisms never gave rise to perni- 
cious symptoms. Celli 80 states that the tertian and quartan 
parasites never cause pernicious fevers. Marchiafava and Big- 
nami 162 say that there is no instance on record of a malignant 
fever following tertian and quartan infections, and that no 
autopsy has ever been made in connection with a malignant 
spring tertian or quartan. Mannaberg, 141 Van der Scheer, 163 
and Maurer 135 believe that only the estivo-autumnal parasites 
have a role in the production of the pernicious fevers. Thayer, 
in his "Lectures on the Malarial Fevers," says that he never 
heard of a pernicious paroxysm occurring in tertian or quartan 
infections, with the exception of the case of French. 

While the vast majority of cases of pernicious malaria are 

10 r 



I46 THE STUDY OF MALARIA 

due to the infection with the tropical parasites, it cannot now 
be maintained that tertian and quartan infections are not occa- 
sionally accompanied by perniciousness. Craig 164 says that any 
of the malarial parasites may cause pernicious infections, lead- 
ing to death. Crespin 165 informs us that it is not rare to find 
on examination tertian and quartan parasites in these cases. 
Billet 151 found the large tertian in 6 of 40 cases of typhoid 
pernicious. Ziemann 96 observed a case of pernicious malaria 
due to the benign tertian. Thiroux 86 found this parasite in 
a case of convulsive pernicious in a mulatto infant. Ewing, 27 
in 64 cases of the cerebral type of pernicious, found the large 
tertian parasite alone in 5. French 166 reports a case of coma- 
tose malaria in a man, aged twenty-one, whose blood harbored 
the tertian parasite. Hunt 167 observed a case of common tertian 
complicated by alarming hematemesis in a boy aged eleven. 
McElroy 168 had a case of comatose pernicious due to tertian 
infection in a negro male, aged thirty. Ficucci 369 records a 
case with a pernicious meningo-cerebellar syndrome due to 
tertian parasites. Fenner 170 gives the history of a case of the 
comatose type in an adult; the blood examinations showed 
crescents and large tertian forms. 

Craig 1,64 makes the assertion that quartan infections are 
more apt to become pernicious than tertian. The writer, how- 
ever, agrees with Davidson, 66 who says that pernicious symp- 
toms occur more rarely in connection with the quartan infec- 
tions than with simple tertian. The reasons for this are proba- 
bly the relative rarity of quartan fever and the more even 
distribution of parasites throughout the circulation, there being 
slight tendency to form accumulations. 

It is not yet known with certainty which variety of the 
estivo-autumnal parasite gives rise most frequently to perni- 
ciousness. Marchiafava and Bignami 162 and Mannaberg 141 
hold that the tertian estivo-autumnal infections are the most 
dangerous, only a few cases showing the quotidian. Craig, 70 
however, found the quotidian parasite most often in cases in- 
fected in Cuba and in the Philippines. This was also the expe- 
rience of Wright 38 in British Malaya, who found the pigmented 



ETIOLOGY 147 

quotidian parasite most frequently associated with the cerebral 
and gastro-intestinal types of pernicious malaria. 

The part played by the crescents in the pathogenesis of per- 
nicious paroxysms is worthy of brief consideration. Marchia- 
fava and Bignami, 22 Celli, 80 Mannaberg, 141 A. Plehn, 171 
Koch, 172 Manson, 59 Thayer, 98 and others believe that this form 
of the organism is non-pyrogenic. Ewing, 130 however, holds, 
with Laveran, that it is by no means certain that the formation 
and development of the crescents are entirely innocuous to the 
patient. Ewing, doubtless in part, bases this opinion on the 
finding of crescents alone in 33 of 64 cases of cerebral perni- 
cious. 27 Whether the blood examined in these cases was per- 
ipheral or visceral is not stated, but as only three were fatal 
it may fairly be assumed that in most instances at least it was. 
peripheral. That the crescentic form of the parasite has an 
intimate relation to the production of the pernicious fevers is 
improbable, for the following reasons : First, crescents alone 
may be found in the peripheral blood, and intense localization 
of active forms be present in the brain or other viscera. The 
number of parasites in the superficial circulation is not a reliable 
guide to the severity of the attack. Of Ewing's 64 cerebral 
cases no parasites were identified in 11, and in many of his 
33 cases in which crescents alone were found the search was 
successful only after one and two hours. Second, crescents 
are rarely, if ever, present in the parasitic localizations and 
thrombi frequently observed in pernicious cases. 

Of the pathogenetic factors which excite perniciousness the 
following are to be regarded as the most important and ap- 
proximately of relatively equal importance : 

1. An excessive number of parasites. 

2. Localizations of parasites. 

3. Toxins. 

4. Individual predisposition and external etiologic influences. 
Number of Parasites. — Golgi's law, that the number of 

parasites determines the severity of the attack, has been gen- 
erally accepted. Cases in which the parasites are in very great 
numbers in the peripheral blood are usually accompanied by 
coma. 



148 THE STUDY OF MALARIA 

We have no means of estimating even approximately the 
total number of malarial parasites in the body of a malarial 
patient, as the distribution of the former varies within the 
widest limits. They may be numerous in the peripheral and 
visceral circulation generally ; they may be scanty or absent in 
the peripheral circulation and numerous in most of the viscera ; 
or they may exist in moderate numbers or be absent except in 
certain areas where they may be intensively localized. That 
the parasites are abundant, either absolutely in the body as a 
whole or relatively in certain areas, probably holds good in 
a great majority of the cases, though, as Celli 80 states, we 
cannot always attribute perniciousness to the large number 
of parasitic forms. Marchiafava and Bignami 22 call attention 
to certain grave cases of comatose, convulsive, delirious or 
mixed pernicious, in which from beginning to end and even 
at autopsy very few parasites are found. Mannaberg 141J says : 
"From the general impression which I have obtained naturally 
from the peripheral blood, the number in malignant fevers is 
perhaps larger, yet the difference scarcely seems so decided as 
to make this factor alone responsible for the perniciousness." 

As applied to the number of parasites in the peripheral blood, 
Golgi's rule is applicable only in a very general sense. Bacelli 173 
says that fatal cases of malaria occur in which there cannot 
be found any known form of the parasite. 

Ziemann 48 states that the number of parasites in the per- 
ipheral blood is not always in direct relation to the severity 
of the attack. Crespin 144 acknowledges that he had difficulty 
in finding the parasites, which were always scanty in these 
cases. He gives the details of a case in which there were 
neither parasites nor pigment in the peripheral blood, but they 
were numerous in the vessels of certain viscera. This writer 
quotes Nocht as saying : "In pernicious attacks the hematozoa 
are not found in the peripheral blood, but only in the viscera." 
Moore 25 says : "I have often seen cases where the symptoms 
in no wise seemed commensurate with the number of parasites 
observed in the specimen of blood." According to Kendall, 30 
there may be only a few parasites in the peripheral circulation, 
or it may be even impossible to find them. Mannaberg 141 states 



ETIOLOGY 149 

that it sometimes happens that the peripheral blood is very 
poor in parasites. Marchiafava and Bignami 22 note the fact 
that the contradiction found so often during life between the 
number of the parasites and the gravity of the disease dis- 
appears when an autopsy allows of an examination of all the 
organs. Craig 70 asserts "that the number of the parasites 
found in the peripheral blood is not always a criterion as to 
the perniciousness, as one of the most rapidly fatal cases I 
have ever observed showed but few parasites in the peripheral 
blood." To quote Barker : 174 "In the estivo-autumnal infections 
the number of organisms circulating in the peripheral parts 
affords, as a rule, very insufficient data upon which to base 
an idea of the severity of the infection." Thayer 98 says that 
there may be very few parasites in the peripheral circulation. 
He mentions a fatal case of the comatose variety showing no 
active parasites in the peripheral blood and only a few ovoids 
and crescents after a careful search of the blood, obtained by 
puncture of the spleen. Marchoux 105 reported 3 cases of perni- 
cious malaria in which the parasites were very scanty in the 
peripheral circulation. Zeri L75 records 4 cases of pernicious 
fever in all of which the parasites were few in number. Bloom- 
bergh and Coffin 176 treated a case ending fatally in which no 
parasites could be found until forty-eight hours after onset, 
notwithstanding repeated examinations. In 7 cases in which 
Fenner 170 examined the blood no parasites were found in 5. 
Ewing's 27 1 1 cases of the comatose form, in which no parasites 
were identified, have been mentioned. The writer has observed 
1 case of severe comatose malaria in a boy, aged twelve, in 
whose peripheral blood the parasites were scanty. 

On the other hand, the superficial circulation may be teem- 
ing with parasites, while the patient experiences only a mild 
attack. Thus A. Plehn" gives the histories of 2 cases in which 
the symptoms were slight though the peripheral blood showed 
as many as thirty-five and forty-six tropic parasites, respec- 
tively, to each field of the microscope. 

It is highly probable that an enormous number of parasites, 
equally distributed, depends for their power to elicit pernicious 
symptoms upon the increased quantity of toxin elaborated. 



150 THE STUDY OF MALARIA 

Localizations of Parasites. — Accumulations of parasites in 
the brain were first described by Planer (1854), and by Fre- 
richs (1861) ; those in the liver by Guarnieri (1867). More 
recently the minute observations of Marchiafava and Bignami, 
Dock, Barker and Ewing have taught us that pernicious mala- 
ria, in many of its varied manifestations, is dependent on 
these localizations in one or more of a multiplicity of localities. 
Localizations in the brain have been found associated with a 
wide variety of cerebral symptoms; in the mucosa of the ali- 
mentary tract, the gastro-intestinal symptoms, and typical algid 
attacks; in the heart, with cardiac symptoms; in the medulla, 
with bulbar paralysis; in the retina, with amblyopia; in the 
pancreas, with hemorrhagic pancreatitis, etc. In proportion to 
the amount of damage sustained by the kidneys in malaria 
there is less tendency for parasites in pernicious attacks to accu- 
mulate in these organs than in any other of the body. The 
most carefully studied case of this condition is that of Ewing. 177 

These localizations consist, in the main, of parasite-infected 
red blood-cells. There may be, however, pigmented leucocytes 
and free parasites and pigment. The parasites in each particu- 
lar case may be of the same or of different stages of develop- 
ment. The pigmented and sporulating forms are probably 
oftenest seen, but the earlier phases are frequently observed. 
It would seem reasonable that the crescents, on account of their 
size, would frequently form an important element in these accu- 
mulations of parasites, but such does not appear to be the case. 

The cause of the parasitic concentrations is problematical. 
It cannot be due to the size, weight or loss of elasticity of the 
infected cells, for, as Mannaberg 141 states, the benign parasite 
would be more apt to form thrombi if this were the cause. 
Kelsch and Kiener 178 and others have observed endothelial 
swellings in the small cerebral vessels, with consequent constric- 
tion of calibre, but whether this is a cause or an effect cannot 
be said. Vasomotor disturbances and phagocytosis have also 
been invoked in explanation. The most probable theory is that 
of Mannaberg, 141 who attributes the condition to a sort of 
agglutination or adhesiveness that holds the erythrocytes to 
the vessel walls. 



ETIOLOGY 151 

The symptoms present in cases in which, on post-mortem 
examination, localizations of parasites are demonstrated are not 
always referable to these aggregations alone, since changes are 
frequently observed which are secondary to parasitic throm- 
bosis, and may outweigh the latter in pathogenic importance. 

The most conspicuous of these changes are perivascular exu- 
dation, hemorrhage and necrosis. The hemorrhages are usu- 
ally punctate, but Blanc 179 and Ziemann 48 report large cerebral 
clots. 

This propensity of the parasites in pernicious fever to con- 
gregate undoubtedly explains the course of many cases, but 
by no means all. Fatal cases of comatose malaria have been 
observed with no parasites at all in the brain. Ford 180 reports 
a case with serious pulmonary symptoms in which the parasites 
were no more numerous in the lung than in the general circu- 
lation. "The severity of the renal lesion, with the absence of 
parasites in the renal vessels, also requires mention." 181 

It is not known whether parasitic thrombi may exist without 
producing symptoms. Frerichs, 96 who frequently observed 
thrombotic occlusions of the cerebral vessels, insisted that too 
much stress should not be laid on them on account of the rich 
collateral circulation. He likewise affirmed that he had more 
than once seen markedly pigmented brains without cerebral 
symptoms during life. 

Based on a case in which the patient was suddenly attacked 
with transient coma three times in five days, Ewing 181 believes 
that the embolic processes are factors in some instances. 

This is the most probable explanation of these cases. 

Toxins. — The evidence of the existence of a toxin in malaria 
has been detailed above. 

Individual Predisposition and External Etiologic Influ- 
ences. — "We ought, then, in cases of pernicious fever, to seek 
in the conditions of the ground, whose quality is so different, 
and not in the quantity of the seed, the reason which shall ex- 
plain to us the gravity of the disease." 157 

The quality of the soil, in the sense so aptly employed by 
Homem, as a factor in the pathogenesis of pernicious malaria 
has probably not received the attention it deserves. This influ- 



152 THE STUDY OF MALARIA 

ence, in many instances, doubtless not only induces the attack, 
but determines its type. Organs or systems enfeebled by ante- 
cedent ailments are apt to play the title role in the pernicious 
tragedy. Thus algid and choleraic attacks may be associated 
with a history of intestinal catarrh ; the comatose and delirious 
cases, with a history of abuse of alcohol; the convulsive with 
epilepsy, etc. It is not improbable that some cases of dysenteric, 
cardialgic, syncopal, tetanic, cataleptic, paralytic, pneumonic, 
pleuritic, gastralgic, and other forms described by the older 
writers may be similarly explained. Mercier 1S2 goes so far as 
to say that all pernicious attacks are merely visceral complica- 
tions. 

Malarial subjects who are much exposed to the heat of the 
sun are liable to be stricken with pernicious fever, especially of 
the cerebral type. This danger is enhanced if to the solar heat 
are added fatigue, deficient or improper food, or other hard- 
ships. Certain psychic states have causative significance. 
Hertz 183 states that he has seen the localization of pernicious 
symptoms determined by injuries of the skull through a fall 
or a blow. 

In addition to the four principal factors enumerated, con- 
gestion of viscera and parasitic obstruction of the hepatic capil- 
laries have been regarded as important. It is probable that they 
have little influence. 

A feeble phagocytic activity was considered by Golgi as 
predisposing to pernicious attacks. In the present state of our 
knowledge it is impossible to define the relation of this func- 
tion to perniciousness. 

A consideration of the relative frequency with which the 
several factors are concerned in the pathogenesis of the various 
forms of pernicious malaria will necessarily be brief. In the 
comatose variety any of the four chief agents may take part; 
idiosyncrasy and external influences may unite with any of the 
other factors; an extraordinary number of parasites in the 
general circulation, without accumulations in the brain, is pro- 
ductive of coma probably because of the toxin. Ewing 181 says 
that the majority of cases of comatose malaria coming to 
autopsy do not show a massing of parasites in the brain. He 



ETIOLOGY 153 

attributes these cases to general toxemia. However, a study 
of the autopsy records of Marchiafava and Bignami 162 shows 
that in a great majority of their fatal comatose cases the para- 
sites were markedly localized in the brain. Davidson 06 and 
Ruge 158 believe that almost always the cerebral capillaries are 
found filled with parasites in those who have died with coma. 

Other pernicious cerebral forms are usually associated with 
parasitic localizations. 

The algid variety, while possibly sometimes dependent on 
toxemia, is usually due to a massing of parasites in the gastro- 
intestinal mucosa. This is explained by Davidson 66 as follows : 
"Experiments show that the alimentary tract is in closer con- 
nection with the cardio-inhibitory center than other parts of 
the body, and that irritation of this tract, if sufficiently power- 
ful, will produce cardiac inhibition, with pallor of the surface 
and accumulation of the blood in the abdominal vessels. That 
the intestinal canal is the center of mischief in this form of 
pernicious attack will appear all the more probable if we ob- 
serve the character of the disturbances so frequently associated 
with the algid condition — the cardialgic pain, the choleraic 
vomiting and purging, and the dysenteric discharges." 

ETIOLOGY OF HEMOGLOBINURIG FEVER 
Etiologically hemoglobinuric fever stands in the same rela- 
tion to malaria as do tabes and dementia paralytica to syphilis, 
and may, very properly, be regarded as a "paramalarial" infec- 
tion. 

Among the conditions other than blackwater fever under 
which hemoglobinuria can occur may be mentioned paroxysmal 
hemoglobinuria, scarlet fever, typhus and typhoid fevers, acute 
articular rheumatism, leukemia, pneumonia, streptococcus in- 
fection, chronic suppurative conditions, after extensive burns 
or freezing, occasional injuries, rupture of ectopic pregnancy, 
transfusion of blood, injection of tuberculin, poisoning with 
phenocoll, guaiacol, pirodin, salipyrin, salicylic acid, antipyrin, 
sulphonal, the salts of chloric acid, phenol, pyrogallic acid, sul- 
phuric, nitric, and hydrochloric acids, naphthol, analine, chrys- 
arobin, toluylendiamin, glycerine, nitrobenzol, potassium chlo- 



154 THE STUDY OF MALARIA 

rate, phenacetin, arseniuretted hydrogen, methylene blue, phos- 
phorus, oxalic acid, certain illuminating gases, helvella escu- 
lenta, and snake venom. Hemoglobinuria is a common symp- 
tom of Texas fever in cattle, and is seen occasionally in sheep, 
dogs, goats, horses, and mules, following infection with hema- 
tozoa resembling the malarial parasite. 

Race. — Hemoglobinuric fever is chiefly a disease of the 
white race. The negro is not absolutely immune, though not a 
few observers of wide experience have not seen cases in this 
race. This relative immunity can be explained only by natural 
selection. It varies markedly in different tribes, and members 
of an insusceptible tribe may be attacked on moving to a black- 
water fever focus. F. Plehn 5 refers to an extensive outbreak 
that occurred among the Cameroon negroes, especially those 
who came from the interior to the coast. According to Drye- 
pondt, 86 the negroes recruited for the Congo Free State in 
1890 to 1892 paid a large tribute to this malady. DeGreny 8 
saw 20 cases in negroes imported from the British Antilles for 
railroad construction work on the lower Congo. In the medical 
report from German East Africa for the official year, 1903-4, 
there were listed 8 cases in negroes. Corre, 8 Donny, 8 the 
younger Moncorvo, 8 Hanley, 184 A. Plehn," Rudolph Plehn, 185 
Wittrock, 49 Brunn, 49 Curry, 180 Eyles, 101 Doering, 187 Reynolds, 188 
Easmon, 101 Wicke, 90 Gaertner, 90 Ouartey-Papafio, 101 O'Sulli- 
van-Beare, 90 Vieth, 90 Goltman and Krauss, 189 McElroy, 190 
Berenger-Feraud, 191 Ziemann, 86 Fisch, 191 Ollwig, 51 Greisert, 51 
Lewis, 192 Francez, 193 Minor, 194 McKay, 195 Tyson, 196 Gorgas, 32 
and Wendland 49 have seen cases in negroes. The writer has 
seen two cases in mulattoes and two in black negroes. Chinese 
imported into blackwater fever regions are almost as suscepti- 
ble as whites. Manson 59 says that many of the Chinese labor- 
ers on the Congo railway died of hemoglobinuric fever. Im- 
ported Indians are affected, but, according to Daniels, 197 are 
only about one-fourth as susceptible as Europeans. As may 
be inferred from one of the names, "fievre jaune des Creoles," 
Creoles are not infrequently attacked. Masterman 04 reports 
that it is common among the Jews of Palestine. Rothschuh 8 
saw cases in mixed breeds and pure Indians in Nicaragua. 



ETIOLOGY 



155 



Sex. — Males are more often stricken than females, the lat- 
ter being less often exposed to malarial infection. In the tem- 
perate zone the proportion of males to females is about 3 
to 1. In persons under fifteen the proportion is more nearly- 
equal. As we approach the equator the difference becomes 
wider, owing to the relatively small number of susceptible 
females and children. Daniels 57 says the proportion of male to 
female cases in British Central Africa is 15 to 1. Car- 
damatis 198 believed that pregnancy conferred immunity; how- 





























^|]U||U 
































Si 






























■ I'l j 1 II 1 II II 1 








V ' 


?i|:: 




— L 














4- 


It:: 


— \- 










W 






1 

mffffflff 








Ml* 


::± 








~xi 










it: 


;±ffiii]Mi 
































































































































j | 


: | | lllllll 


| 
























■ 1 1 |J| M f 1 ( 1 1 1 


| 








■ + ' — ■ 


:: :x: 














1 1 l/l 1 1 1 II 1 1 1 




' 


^—r 




:±:S:: 


::::iE~ 














■ ill 






' 




=+:-: 










ifmff 






I 




; 1 1 1 
















wt 








: J Ml J 






































iiiii! 










1 1 1 III | 

|f 
'111 

Wffff 


1 


mil 


-rF 
1 1 


m 



Fig. 50. — Age distribution of blackwater fever in America. 



ever, Krauss 199 has reported a case in a pregnant woman, who 
made a tedious recovery after abortion. The writer 200 re- 
cently published brief notes of a case occurring in the practice 
of a colleague. The woman aborted on the third day of the 
disease and died on the fourth. Cases have often been observed 
to follow immediately after menstruation. 

Age. — In America more than half the cases occur before 
the age of thirty, though very young children are relatively 
exempt. In the tropics it is commoner in the third and fourth 



156 THE STUDY OF MALARIA 

decades of life because most of the susceptible population is 
within these ages. Daniels 57 saw a case in a half-caste about 
five years old; Wendland, 49 Van der Scheer, 2ni and Karamit- 
sas 15 observed cases in children of four; Lipari 202 mentions 2 
cases in children of three; Masterman 64 1 in a girl of two, and 
Oetker 52 1 in a two-year-old child; Fisch 203 saw cases in chil- 
dren of fourteen months and two and one-half years, and 
McElroy 204 1 at twelve months. 

Season. — In the tropics, like malaria, it is perennial, occur- 
ring without marked seasonal prevalence, though probably com- 
moner in the transition period from the moist to the dry season. 
In the temperate zone it appears at the height of, or immedi- 
ately following, the malarial season, the second half of the 
year showing by far the greater number of cases, especially 
August, September, and October. A few cases are seen in the 
first six months. In Greece it is during the months of Novem- 
ber and December that the majority of cases occur. 

Family Predisposition. — Tomaselli 205 believed in a well- 
marked family tendency, having observed cases in several mem- 
bers of the same family. Daniels 57 refers to three families in 
which he noticed this predisposition. Three such families are 
known to the writer. Cardamatis 206 relates the case of a family 
of seven, of which the father, mother, and one daughter were 
within a few days attacked and died with blackwater fever. 
The others, removing to Athens, were all subsequently at- 
tacked, but fortunately recovered. Nine years later a daughter 
had the fever again and recovered. Sutherland 168 speaks of a 
family of which all the children, six in number, died with 
hemoglobinuric fever. 

Idiosyncrasy. — An idiosyncrasy in susceptible individuals 
has long been assumed and by many passively accepted as the 
sole explanation of the mysteries of pathogenesis. Foustanos 207 
holds that idiosyncrasy is either congenital or acquired, as the 
result of debility or bodily changes due to syphilis, malaria, 
etc. There is not sufficient evidence to show that heredity 
plays an important part in whatever is meant by this vague 
term. 

Previous Attacks of Hemoglobinuria. — Who has had 



ETIOLOGY 157 

blackwater fever is prone to have recurrences. In the tropics 
about one-fourth of the subjects have more than one attack. 
Of 304 cases mentioned by Cardamatis, 81 occurred in persons 
who had previously had it. Several tropic physicians record 
repeated attacks in themselves. Thus F. Plehn 208 had five at- 
tacks, Crosse 209 at least ten severe attacks, and Banks 210 twelve 
or thirteen during eighteen years' residence in Congo. One of 
Koch's 172 patients had ten attacks in one year, and the Plehns 211 
state that they know persons who have had fifteen or more 
attacks. There is, therefore, no active immunity; the only 
immunity except natural being conferred by prolonged resi- 
dence in an endemic focus. 

Length of residence in the home of the disease is an impor- 
tant factor. A curve showing the number of first attacks to 
each year of residence would rise from the first to the third 
years and then fall gradually. This is almost constant for 
observation in the tropics, being less noticeable in temperate 
regions. The following table of cases seen in the tropics will 
illustrate : 

First Second Third Fourth Fifth L t 
year. year. year. year. year. 

Burot and Legrand, 211 100 cases ... . 6 22 43 20 .. 9 

Daniels, 67 114 cases 21 40 27 12 5 9 

Berenger-Feraud/ 6 185 cases 10 42 79 37 9 8 

Vedy, 2is 54 cases J> 8 29 _5 J? _4 

43 112 178 74 16 30 

Fifty cases observed by McElroy 214 in the Mississippi Valley 
were distributed as follows : Two in the first year of residence, 
3 in the second, 6 between the second and the fifth, 23 between 
the fifth and the tenth, 1 1 between the tenth and twentieth, and 
5 after twenty years. 

Exceptionally are cases seen after only a short period of 
tropic residence, as Plehn's 5 Case XXXV, after two months in 
the Cameroon, and one of Brem's 215 cases, after two months on 
the Isthmus of Panama. Ziemann 48 mentions 2 cases begin- 
ning six weeks and twenty-seven days, respectively, after arri- 
val in a malarial locality, and Oeconomou 15 observed a case 
occurring after ten days of residence in a malarial region. The 
case showing the longest period of residence before onset in 



I58 THE STUDY OF MALARIA 

which this is specified is that of Howard, 216 twenty-three years 
in Central Africa, though in 5 of McElroy's 214 cases the length 
of residence was longer than twenty years. 

Altitude. — Hemoglobinuric fever is often considered a 
disease of the lowlands, though cases are commonly observed 
at heights of 3,000 feet. The results of Daniels' 57 observations 
on the influence of altitude may be stated as follows : 

The greater number of recorded cases have occurred in the 
highlands at or about 3,000 feet above the sea level. There 
are two reasons for this : First, the number of residents in 
these highlands is much greater than in the other districts. 
This correction alone reverses the figures; secondly, many of 
these cases were visiting the highlands on account of health or 
for other reasons. Others were passing through the highlands 
when invalided home. Some had recently visited the lowlands. 
A true correction that would attribute each case to the district 
in which the disease was acquired is impossible, but taking an 
arbitrary period of a fortnight as representing a not improbable 
latent period we should find that the place of residence a fort- 
night or more previous to onset would give a very different dis- 
trict distribution to that given by considering the place of onset. 
Corrected for proportional numbers of susceptible persons in 
each district and for place of residence two weeks previous to 
onset, the distribution per 10 of population is as follows: 1.04 
in the highlands, 7.28 at the lake level (Lake Nyassa, altitude 
about 1,500 feet), and 3.8 in the lower shire regions. Accord- 
ing to Laveran, 1 it was necessary, on account of the frequency 
of blackwater fever, to abandon certain posts in Congo estab- 
lished at heights of 500 to 700 meters. 

Change of residence is a not uncommon cause for an out- 
break, especially if the difference in altitude or climate is de- 
cided. In Africa not only those coming from the mountains 
to the lowlands, but also those moving from the insalubrious 
littoral to the refreshing high-lying districts are predisposed. 
This change seems to be independent of the hardships of travel. 

After Leaving Endemic Region. — Such cases have been 
observed in England by Bassett-Smith, 217 Hughes, 218 Sylivan, 8 
Crosse, 4 Manson, 219 Daniels," and Parker; 220 in Ireland by 



ETIOLOGY 159 



223 
225 



Mowbray; 221 in Germany by Schlayer, 222 A. Plehn, 24 Kleine, 
Koch 224 and F. Plehn; 211 in France by Burot and Legrand, 
Le Dantec, 226 Kelsch and Kiener, 178 Rouvier, 227 Vincent, 8 Bois- 
son, 86 Troussaint 86 and Laveran; 1 in Belgium by Dryepondt 
and Vancanpenhout 228 and Bertrand; 229 and in Baltimore by 
Brem. 215 Many of these cases were not mere relapses ; indeed, 
in the majority in which the number of previous attacks was 
specifically stated they were first attacks. The onset may occur 
from a few days to five months or more after leaving the 
endemic area. Inclement weather and fatigue seem to be 
factors in some of these cases. The mortality is low. 

Occupation which requires residence in a malarial locality 
and which necessitates overturning of the soil, as gardening, 
farming, ditching, railroad construction, etc., is largely pre- 
disposing. Not a few cases occur among timber workers. 
The disease prevailed extensively among those engaged in the 
construction of the canal of Corinth. Manson 59 tells us that 
many of the Chinese laborers on the Congo railroad died of 
hemoglobinuric fever, and DeGreny 8 found many cases in both 
negroes and whites in the railroad work on the lower Congo. 
Crosse 209 says that it is significant that his first three gardeners 
died of blackwater fever, and that for some considerable time 
cases occurred only near the plantations, and as the plantations 
became more numerous the disease spread to the other stations 
in the territories. 

Occasional Causes. — Of these, exposure to cold and damp- 
ness is probably the most efficacious, showing somewhat analo- 
gous to paroxysmal hemoglobinuria. Overexertion precedes 
some cases. The influence of alcohol has probably been over- 
estimated. Trauma has a slight etiologic importance. Thus 
Mould 230 mentions a case developing after a sprained ankle; 
Plehn 61 one in which a man was wounded in a bush fight and 
bled considerably. Crosse 209 and Plehn 5 saw cases immediately 
following confinement. Psychic states, as anger, grief, and 
fear, exposure to sun, fatigue, excessive venery, syphilis, and 
the mercury cure have been mentioned as occasional causes. 
Cardamatis 86 lays stress on the association with rheumatic 
diathesis, 12 of his 30 cases being rheumatic. Alexander 



l6o THE STUDY OF MALARIA 

Haig 231 believes there is an intimate relation, most probably 
causative, between an excess of uric acid in the blood and 
hemoglobinuric fever. He makes the unfounded statement 
that the ordinary acid sulphate of quinine is about one-fifth 
xanthin, which is physiologically and pathologically equivalent 
to uric acid, and herein, he believes, lies its supposed power to 
produce hemoglobinuria. Johnson 60 holds that a meat diet pre- 
disposes to blackwater fever. 

Previous Malaria. — It may be said with almost absolute 
certainty that previous infection with malaria is essential. In 
fact, a majority of careful observers make the unqualified 
assertion. The extreme rarity of cases in which preceding 
malarial infection is denied almost forces us to the conclusion 
that it may have been overlooked, as might occur in latent or 
masked infection. It is, however, not impossible that hemo- 
globinuria may exceptionally accompany the first outbursts of 
malaria, as in cases of F. Plehn, 5 Goltman and Krauss, 189 and 
Brem. 215 In all of the cases of Tomaselli and Koch, the most 
ardent advocates of the quinine theory, there was a history of 
antecedent malaria. Tomaselli 205 states in italicized words that 
the two conditions which favor the hemolytic action of quinine 
are: i, Malarial infection, chronic or sometimes recent; 2, a 
special idiosyncrasy often hereditary. 

Cardamatis 206 cites several writers who have seen cases with- 
out preceding malaria, and Van der Scheer 201 is said to have 
seen such a case. 

Pathogenesis. — There are three chief theories as to the 
nature of hemoglobinuric fever: 1, that it is malaria; 2, that 
it is quinine poisoning; 3, that it is a disease sui generis. 

I. Against the malarial nature of hemoglobinuric fever may 
be urged the following objections : 

1 . The parasites are often absent ; when present they are not 
numerically proportionate to the severity of the attack, and 
usually disappear as the disease progresses; sporulation does 
not correspond in time with the symptoms; hemoglobinuria 
may be associated with different forms of the malaria parasite. 

2. In malaria very numerous parasites may be present with- 
out producing hemoglobinuria. 



ETIOLOGY l6l 

3. The geographic range does not coincide with that of 
malaria.. 

4. Its seasonal prevalence does not correspond with that of 
malaria. 

5. Blackwater fever is not amenable to quinine. 

The frequency with which the parasites are found is shown 

by the following list of examinations by various observers. 

The first column of figures shows the number of examinations 

made, the second the number in which the parasites were 

present : 

Kanellis 232 20 10 

Bignami and Bastianelli 233 2 1 

Vincent 8 5 1 

Dryepondt and Vancanpenhout 228 1 o 

Powell 234 11 5 

Koch 172 16 2 

Hanley 184 13 

Cardamatis 1 '' 3 25 4 

Burns 235 3 3 

Boisson 89 3 3 

Daniels 57 16 4 

Wellman 56 I 1 

Crosse 236 1 1 

Brem 215 14 2 

Krauss 199 11 7 

McElroy 214 23 9 

Thin 237 1 

Kleine 223 15 6 

Hoffman 49 3 2 

Curry 186 2 o 

Troussaint 86 7 5 

Pezopoules and Cardamatis 86 7 3 

Ketchen 233 1 1 

Mastermann 64 1 1 

Schlayer 222 I 1 

Ollwig 49 15 6 

Stephens and Christophers 57 16 3 

Howard 218 1 o 

Ruge 239 1 1 

Goltman and Krauss 189 12 4 

Woldert 240 1 1 

Hartsock 241 1 o 

F. Plehn 5 ^3 22 

Broden 242 20 6 

Marchoux 243 9 1 

Oeconomou 243 3 

Cardamatis 244 25 4 

Le Dantec 226 3 o 

Bernardo 245 20 17 

Gauducheau 245 15 o 

Da Costa 245 20 15 

Grattan 246 11 4 

Kulz 247 16 3 

Kudicke 51 17 9 

Wellman 68 34 3 

11 



l62 THE STUDY OF MALARIA 

As stated in the first objection, the parasites when present 
tend to disappear as the disease progresses. The following 
figures show the difference in results of examination at differ- 
ent periods. The great frequency with which they are found 
the day before the attack should be noted : 

Stephens and Christophers : 118 

Day before attack parasites present in 95 per cent, of cases. 
Day of attack parasites present in 70 per cent, of cases. 
Day after attack parasites present in 20 per cent, of cases. 

Mannaberg : m 

Day before attack parasites present in 95.6 per cent, of cases. 
Day of attack parasites present in 63 per cent, of cases. 
Day after attack parasites present in 17.1 per cent, of cases. 

The reasons for the rapid disappearance of the organisms 
are, first, that often quinine has been taken before the examina- 
tion; secondly, that in the terrific hemolysis the weaker cells, 
including those containing parasites, are usually the first to 
succumb. 

The hemoglobinuria occurring in Texas fever of cattle is 
cited with some show of reason as an argument for the purely 
malarial origin of blackwater fever. There are essential dif- 
ferences, however, in the occurrences of blackwater in malaria 
and Texas fever. First, malaria is followed by blackwater in 
a very small percentage of cases, malaria being common, hemo- 
globinuric fever much rarer; in Texas fever blackwater is a 
common symptom, occurring in nearly all severe cases. Second, 
in blackwater fever in man the number of parasites shows no 
proportion whatever to the severity of the disease. In Texas 
fever, on the other hand, as is shown by Smith and Kil- 
bourne, 248 the number of parasites is in direct relation to the 
severity of the process and increases as a fatal termination 
approaches. In human malaria the parasites may exist in very 
large numbers without the development of hemoglobinuria; 
this is not the case in Texas fever. Bonome found in the 
icterohemoglobinuria of sheep the same relation between the 
number and behavior of the hematozoa and the intensity and 
progress of the attack as obtains with Texas fever. 

The form of parasite found in blackwater fever is, in the 
great majority of instances, the estivo-autumnal. Only excep- 



ETIOLOGY 163 

tionally is hemoglobinuria combined with infections with the 
benign organisms. . The tertian parasite has been observed in 
cases of Ziemann, 48 Panse, 79 Orme, 249 Pecori, 69 Carducci, 69 Van 
der Horst, 250 Hughes, 218 Koch 234 (5 cases), A. Plehn" (3 
cases), Ollwig, 49 McElroy, 214 Goltman and Krauss, 189 Brem, 215 
Herrick 251 and Curl 251 (3 cases). The quartan parasite has 
occurred in cases of Vincenzi, 96 Grocco, 96 Kleine, 223 Kudicke, 51 
and Otto. 53 Thiroux 86 and Laveran 11 are said to have found 
the large form of parasite,, but whether tertian or quartan is 
not stated. The fact that parasites other than estivo-autumnal 
have been found is no argument against the malarial nature 
of blackwater fever, since cases of pernicious malaria in which 
only the large tertian parasites were found have been reported 
by French, 166 Ewing 181 (2 cases), Ziemann, 48 and others. 

Some writers believe that in addition to the mechanical de- 
struction of the red cells by the parasites the latter give off 
toxins which have hemolytic powers. The facts, however, 
that intense hemolysis may occur with very few parasites in 
the blood, and that the parasites when present do not bear a 
direct relation to the severity of the disease, but rapidly dimin- 
ish as the disease progresses, speak strongly against the role 
of a parasitic toxin in blackwater fever. 

The number of cases in which the parasite is found if the 
examination is made early constitutes conclusive evidence of 
an intimate relationship to malaria. This, however, is not all. 
The testimony furnished by the parasites is corroborated by 
the two subsidiary evidences of malaria : first, pigmented leuko- 
cytes; secondly, mononuclear leukocytosis. Given, therefore, 
the presence of the parasites in the first hours of attack, and 
the almost constant finding of pigmented leukocytes and 
mononuclear leukocytosis, it is impossible to deny that malaria 
plays an important role in its production. 

The peculiarity of the geographic distribution of hemo- 
globinuric fever is no argument against its malarial nature. 
While it does not occur in all, even highly, malarial countries, 
it is not met except in markedly miasmatic regions. Neither 
does the distribution of quartan fever or some forms of perni- 
cious fever coincide with that of malaria in general. Nor is 



164 THE STUDY OF MALARIA 

the slight difference of seasonal prevalence of any weight. 
The different forms of malaria have different seasons of preva- 
lence, as "spring tertian," and estivo-autumnal. 
Favorable, therefore, to malarial character are : 

1. Geographic distribution. 

2. Length of residence in endemic region. 

3. Previous attacks of malaria. 

4. Malarial prophylaxis is prophylactic of black water fever. 

5. Blood findings : parasites, pigmented leukocytes, mono- 
nuclear leukocytosis. 

The fact that hemoglobinuric fever does not respond to 
quinine is one of the strongest evidences that it is not an attack 
of malaria {per se). 

The writer's opinion of the relation of malaria to blackwater 
fever is that the former is essentially and solely the predispos- 
ing cause, and that in some cases it may also act as the exciting 
cause. 

II. Tomaselli first published his observations as to the etio- 
logic relation between quinine and blackwater fever in 1874. 
More recently Koch has directed attention toward it. The 
widespread controversy that followed the publication of Koch's 
views was bitter in the extreme; the matter was even aired in 
the London lay press. The misunderstanding was probably 
due to two causes ; first, ignorance of Koch's utterance at first 
hand ; secondly, the somewhat non-committal manner in which 
he expresses his idea of the relation to malaria. While he is 
very emphatic that blackwater fever is not an attack of 
malaria, he is not clear as to the predisposing role of the latter. 
He does not even assert that quinine is the exciting cause in all 
cases, but admits that, although he saw no cases of blackwater 
fever in which quinine could be excluded, he could not go so 
far as to maintain that every case of blackwater fever is 
quinine poisoning. 172 There is no doubt but that this acrid 
dispute was productive of dire results, inasmuch as it brought 
the specific into discredit not only with the laity, but with 
many of the profession. Even yet it is necessary in some places 
on account of a fear of hemoglobinuria to disguise quinine 
before it can be given. 



ETIOLOGY 165 

Tomaselli 205 was able to collect from the literature only 102 
cases of quinine hemoglobinuria. 

The objections to the quinine theory are: 

1. Hemoglobinuria is restricted in geographic range, and 
is absent from some highly malarial localities where much 
quinine is used. 

2. Hemoglobinuria does not follow the administration of 
quinine for maladies other than malaria. 

3. In a considerable number of cases the antecedent use of 
quinine can be eliminated with certainty. 

4. The same individual may have an attack following the 
administration of quinine, and later take it without harmful 
results. 

5. The severity of the attack bears no relation to the size 
of the dose. 

6. One dose of quinine could not cause intermittent hemo- 



globinuria. 



7. The great majority of cases recover even under the con- 
tinued use of large doses of quinine. 

Objections 1, 2, and 6 go to demonstrate that other, and 
probably more important, factors than quinine are at work 
even in cases often attributed to it. Objections 4 and 7 are 
not potent if we assume that only a portion of the erythrocytes 
are susceptible to the effects of quinine, and that all these are 
destroyed by the first dose. Objection 5 proves that in cases 
where an outbreak occurs after quinine it cannot be regarded as 
mere quinine poisoning. The third is the strongest argument 
against the theory that all blackwater fevers are cases of 
quinine poisoning. That quinine is not always the exciting 
cause is fully attested by the numerous cases in which no 
quinine had been given, as observed by Boye, 252 Vedy, 213 Doer- 
ing, 253 Broden, 242 Ellenbeck-Hilden, 254 Legrain, 255 Grail, 250 
Rossoni, 257 F. Plehn, 208 A. Plehn 24 (22 cases), Marchiafava, 234 
Celli, 234 Bastianelli, 234 Beyfuss, 234 Van der Scheer, 234 Seal, 258 
Powell, 234 Von Diesing, 234 Carre, 234 Schellong, 234 Laveran, 1 
Quennec, 234 Navarre, 234 Reynolds, 234 Etienne, 234 Sims, 234 
Donny, 234 Dryepondt, 234 Mense, 234 Rothschuh, 8 Fluit, 8 R. 
Plehn, 185 Dempwolfr, 185 Brin, 185 Crosse, 236 Thin, 237 Stalkarrt, 259 



1 66 THE STUDY OF MALARIA 

Hopkins, 260 Cargill, 261 Mould, 230 Hoffmann, 49 Daniels, 57 Ran- 
kin, 262 Cardamatis 206 (32 cases), Yofe, 86 Moffatt, 263 Schlayer, 222 
Curry, 180 McElroy, 264 DuBose, 265 . Hearsey, 266 Ziemann, 86 
Brem, 215 Bignami, 234 Doering 185 and Shropshire 267 (15 per cent, 
of his cases). The writer has seen 4 cases where quinine could 
be excluded from the etiology. 

Hemoglobinuric fever occurring only in malarial subjects 
and quinine being specific for malaria, it is but a most natural 
sequence of events that a large number of the cases of hemo- 
globinuric fever have developed after the administration of 
quinine. The bare fact that blackwater fever often follows 
quinine is weak evidence for quinine etiology in the face of 
the numerous cases in which previous quinine could be abso- 
lutely excluded. 

When, however, attacks can be produced repeatedly at will 
by a dose of quinine the question assumes a very different 
aspect. Such cases are those of Murri, 268 Hoffman, 49 Koch, 172 
Manson, 213 Ketchen, 238 Hopkins, 260 Bertrand, 229 A. Plehn, 24 
Ollwig, 49 Marsden, 269 Daniels, 57 Kleine, 223 Tomaselli, 205 Vin- 
cenzi, 96 and Grocco. 96 

As stated above, there is no relation between the amount of 
quinine and the intensity of the attack. Ketchen 23S precipi- 
tated an attack, experimentally, with 1 y 2 grains. This patient 
stated that one-eighteenth of a gram had previously produced 
blackwater. Karamitsas, 86 Chomatianos, 86 Pampoukis, 86 Kanel- 
lis, 86 Koch, 172 Kleine, 223 Shropshire, 267 Moscato, 86 A. Plehn, 24 
Boxer, 270 and others report outbreaks elicited by less than one- 
half gram. Panse 252 believes that the usual dose preceding an 
outbreak to be from one-tenth to 1 gram. Tomaselli 205 has 
observed attacks to follow the administration of doses as small 
as from one-twentieth to one-tenth gram, and Koch 271 reports 
a case after one-tenth gram had been administered. Kudicke 51 
and Marchiafava and Bignami 22 state the minimum quantity 
as one-twentieth gram, Laveran 1 and Ziemann 48 as 1 centi- 
gram, and Ruge 158 as 1 milligram. 

Tomaselli 205 examined various preparations of quinine to 
ascertain whether the toxic effect was dependent upon adultera- 
tion, and concluded that such was not the case, but that the 



. ETIOLOGY 167 

toxic properties were inherent to quinine itself and to all the 
preparations containing quinine. 

The time intervening between the administration of quinine 
and the onset of hemoglobinuria is almost uniformly fixed by 
various observers at from one to six hours. With six hours 
as the maximum interval, the cases really due to quinine would 
dwindle considerably. 

It is believed by some writers that quinine hypodermically 
does not produce blackwater, even in persons susceptible when 
administered orally. This, however, is not the case. Toma- 
selli 205 has shown that subcutaneous injections of quinine are 
followed more promptly by hemoglobinuria than is the oral 
administration. Kohlbrugge 7 thinks that only the inorganic 
salts of quinine are toxic, and states that the tannate, even in 
the largest doses given to susceptible persons, fails to cause 
hemoglobinuria. McKay 449 has recently attempted to show 
that hemolysis following the administration of the sulphate 
of quinine is due to the sulphate and not to the quinine. This 
view, however, is not supported by clinic experience. Further- 
more, the -results of experiments upon which McKay based 
his conclusion could not be verified by Christophers and Bent- 
ley. It is probable that neither the mode of administration 
nor the preparation used, if absorbed, gives any difference in 
results. 

The role of quinine in hemoglobinuria fever is probably 
highly complex. It will be shown that it is of value as a 
prophylactic when systematically employed; if not thus used, 
and malarial infection be permitted to occur, it may, in some 
persons thus predisposed, act as the exciting cause. In the 
attack itself it is possibly of value in destroying the parasites 
when these are present, or it may act harmfully in aiding hemo- 
lysis. 

Even after a careful study it is not easy to define precisely 
the respective potency of malaria and quinine as etiologic fac- 
tors. To quote Shropshire : 267 "To establish the cause of any 
disease we must apply the agent to the subject, and have, as 
uniform result, the disease. But if there are two agents sus- 
pected as causative which applied together produce the disease, 



1 68 THE STUDY OF MALARIA 

but applied separately to the same individual, the one produce 
it, the other never, we can attribute only to the one a causative 
place, and to the other an accidental presence. Such is the 
case before us. Malaria taken as the cause and applied with- 
out quinine to an individual of such tendency, hemoglobinuria 
results in 15 per cent, of the cases before us. Quinine has 
probably been applied to all the cases before us without the 
presence of malaria and no hemoglobinuria resulting. Which 
produces it?" 

Favoring malaria as against quinine we have : 

1. Antecedent malaria essential. 

2. Relative immunity of the negro. Racial immunity to 
disease well known; racial susceptibility to drugs rare or un- 
known. 

3. Occurs often without the administration of quinine. 

We may safely conclude that the predisposing cause is al- 
ways malaria; the exciting causes are fresh malarial invasion, 
quinine or other medicaments, exposure, exertion, mental 
states, etc. 

III. The most enthusiastic champion of the view that black- 
water fever is neither malaria nor quinine poisoning, but a 
disease sui generis, is Sambon. 121 Manson 272 formerly advo- 
cated this theory. . The two reasons for his belief are a simi- 
larity to paroxysmal hemoglobinuria and an analogy with 
Texas fever. Stalkarrt, 259 Rho, 273 Vincent, s and others be- 
lieve that it is a distinct disease. While the similarity to 
paroxysmal hemoglobinuria cannot be denied, the relation to 
Texas fever, as we have seen, is far from close, and the evi- 
dence that it is a disease sui generis is inadequate. Yersin 274 
found bacilli in the casts and epithelium in the urine of 2 
patients, and believed that he had discovered the cause of the 
disease. Breaudat, 275 however, showed that these were the 
bacillus Coli communis. 

Collet 270 has recently, without grounds, however, suggested 
that there may be a causal relation between the bacillus Mega- 
therium and blackwater fever. 

The theory that green beans and their blossoms were 
the cause of many cases of hemoglobinnric fever seems 



ETIOLOGY 169 

to have perished in Greece, Sicily, and Sardinia, where it 
originated. 

It is generally conceded that hemoglobinuric fever consists 
of a destruction of red blood-cells so widespread that, the 
liver being powerless to transform the liberated hemoglobin 
into bile pigment, the greater part is excreted by the kidneys. 
This conversion into biliary coloring matter is the physiologic 
fate of free hemoglobin, and indeed its pathologic destiny up 
to a certain limit — which, according to Ponfick's postulate, is 
the destruction of one-sixth of the entire number of red cells — 
beyond which hemoglobinuria ensues. This much seems to 
be rather unanimously accorded. The nature of the hemolysin 
is the missing link in the pathogenetic chain. 

The modern study of immunity and cytolysis has thrown 
a flood of light on hemolysis. It is unnecessary to review in 
detail the development of our knowledge of hemolysis, but 
the following facts will be recalled. It has been known for 
some time that the serum of certain animals has the power 
of dissolving the blood corpuscles of certain other animals. 
Bordet showed that this effect may be produced artificially. 
The serum of guinea-pigs naturally has no hemolytic effect 
on the red cells of the rabbit, but if the rabbit's blood is in- 
jected into the guinea-pig and the process repeated the serum 
of the guinea-pig becomes hemolytic toward the rabbit. It 
has been shown that the hemolysins are formed by the inter- 
action of two substances, one, the amboceptor or immune body, 
resisting moderate degrees of heat ; the other, called the com- 
plement, inactivated by a temperature of about 55° C. Neither 
amboceptor nor complement alone is sufficient to dissolve 
erythrocytes, but for this it is necessary that both act, the 
amboceptor sensitizing the cells for the complement. The 
amboceptor may act alone, but the cells will only be rendered 
susceptible, not dissolved. The complement has no effect 
whatever on the red cells except through the immune body. 
The complement exists in normal serum. The formation of 
an anti-hemolysin is thus stated by Wasserman : 27T "Specific 
hemolysin, one, for example, specific for rabbit's blood, de- 
rived by treating a guinea-pig with rabbit's red cells, is highly 



170 THE STUDY OF MALARIA 

toxic to rabbits. Injected into the animals intravenously in 
doses of 5 cc. it quickly kills the animals, causing intra vitain 
a solution of red cells. Such a hemolytic serum then acts the 
same as a bacterial poison. For example, to keep to our illus- 
tration, rabbits are injected first with very small doses of this 
specific hemolytic serum. The dose is gradually increased 
until it is found that the animal tolerates amounts that would 
be absolutely fatal to animals not so treated. If some of the 
serum of this animal is now abstracted and added to the 
specific hemolytic serum it is found that the power of the 
latter will be inhibited. This shows that an antihemolysin 
has been formed." 

These statements refer to the employment of heterologous 
serum; that is, the serum of different species of animals. 
Isolysis, due to the employment of blood of the same species, 
is exemplified in cases following the transfusion of blood 
from man to man. Examples of autolysis, due to the blood 
of the individual, are cases that have occurred after resorption 
of extravasated blood, as the rupture of ectopic pregnancy. 

Based on these facts, which have been amply demonstrated, 
Bignami 22 states his theory as follows : 

1. An alteration in the plasma which is effected, little by 
little, as a consequence of a specific change in the red blood 
corpuscles through which a certain number of them come to 
behave, in respect to the organism, like the corpuscles in the 
blood of another species of animal. 2. The formation in 
consequence of this change of a substance in the plasma which 
is capable, under certain conditions, of becoming hemolytic. 

The writer 278 some time ago modified and elaborated Big- 
nami's hypothesis, and expressed it for the first time in the 
terms of Ehrlich's side-chain theory. 

For the better understanding of the writer's hypothesis the 
pathogenesis may be divided into the following stages: 1, 
erythrorrhexis ; 2, hepatic stimulation and production of ambo- 
ceptors; 3, action of complement; 4, hemolysis and hemo- 
globinuria, or the formation of an antihemolysin. 

1. This primary blood destruction is due directly to the 
malarial parasite, chiefly through the act of sporulation, possi- 



ETIOLOGY 171 

bly also by the production of a toxin. The hemoglobin thus 
liberated is carried to the liver, where it is elaborated into bile 
pigment. We have seen that this erythrorrhexis is insufficient 
to account for hemoglobinuria. 

2. On reaching the liver the hemoglobin is acted upon by 
certain of the molecules or atom groups of the liver-cells, 
which have an affinity for it. When all of the atom groups 
have been combined with by the hemoglobin, which happens 
when this function of the liver has been frequently or recently 
exerted, or when the amount of liberated hemoglobin is very 
large, the liver is stimulated to the production of more such 
atom groups. This stimulation is responded to by an over- 
production of atom groups, some of which gain access to the 
general circulation. Translated into the terms of Ehrlich's 
theory, it may be said that certain receptors of the liver cells 
have the property of transforming free hemoglobin into bile 
pigment; when these receptors are exhausted the deficiency is 
met by overproduction. When the cells become overfilled some 
of these side-chains are cast off into the general circulation. 
Here the receptor becomes an amboceptor. The pathology of 
the liver in this condition fully supports the view of over- 
stimulation. Karyokinesis and other changes in the liver 
cells suggest that it responds to this stimulation. In the pres- 
ent state of our knowledge we cannot determine the chemic 
nature of the immune body. 

3. Having gained access to the general circulation, the 
amboceptor meets the complement which is present in normal 
serum, and the complete hemolysin is formed. 

4. The reaction of amboceptor with complement, if not 
antagonized by an antihemolysin, causes a hemolysis, which if 
sufficiently extensive results in hemoglobinuria. It is highly 
probable that when the production of the hemolysin does not 
proceed with too great rapidity there is formed, parri passu, 
an antihemolysin, which may exactly balance the hemolysin 
without destroying it. This is probably the symbiosis referred 
to by Krauss. 199 So long as the equilibrium between hemo- 
lysin and antihemolysin is maintained no hemolysis occurs, 
but let this equilibrium be greatly disturbed by fresh malarial 



172 THE STUDY OF MALARIA 

invasion, quinine, exposure, fatigue or other, and probably- 
unknown, factors, hemolysis occurs and hemoglobinuria en- 
sues. Under this exact equilibrium the subject may be said 
to possess idiosyncrasy, and is in a condition very similar to 
that of paroxysmal hemoglobinuria. Casagrandi 82 has re- 
cently found in malarial blood a hemolysin the presence of 
which is masked by an antihemolysin. 

It is possible that a slight and temporary loss of equilibrium 
may result in a limited hemolysis producing hemoglobinemia, 
but not hemoglobinuria. In this way may be explained some 
cases of anemia, cachexia, and post-malarial secondary fever, 
in which the parasites, if present, are not in proportion to the 
results. 

It is believed that this hypothesis explains the occurrence 
of hemoglobinuric fever during and after malarial infection, 
with or without the administration of quinine ; it explains why 
the malarial attack may precede by months the appearance of 
blackwater; why exposure, exertion, etc., may elicit an attack; 
why the hemolysis does not always coincide in time with the 
sporulation of the parasites in the cases in which the latter 
are present; it accounts in a measure for the complex relation 
with quinine and explains obscure anemia, quinine fever, post- 
malarial secondary fever, and post-hemoglobinuric fever. 
Lastly, it coincides with the prevalent ideas of tropic physicians 
of an intimate relation between hemoglobinuric fever and 
"biliousness." 

Christophers and Bentley, 279 constituting a committee ap- 
pointed by the Government of India to conduct an inquiry 
regarding the nature of blackwater fever, have recently pub- 
lished an extensive monograph containing a record of their 
experiments and the conclusions which they reached as a re- 
sult of these experiments. They exclude parasitic, osmotic, 
and chemic actions as causes of hemolysis, and show that the 
hemolysin is probably derived from auto-immunization against 
the organism's own red cells, an autolysin, confirming thus 
far Bignami's and the writer's theory. These experiments, 
which are the most complete and convincing that have been 
conducted in connection with hemoglobinuric fever, are too 



ETIOLOGY 173 

extensive to be abstracted, and should be consulted in the 
original by those interested. 

According to the conditions of its occurrence hemoglobin- 
uric fever is classified by the Italian school as follows : 

1. Malarial hemoglobinuria : 

(a) Cases in which the blood contains parasites. 

(b) Cases in which no parasites are present. 

2. Quinine hemoglobinuria in malarial subjects, occurring: 
(a) During the malarial attack. 

(h) After the attack (post-hemoglobinuric). 



CHAPTER IV 

PATHOLOGIC ANATOMY 

ACUTE MALARIA 

The pathognomonic anatomic feature of malaria is intra- 
vascular melanin, which is a product of hemoglobin converted 
through the biologic agency of the malarial parasites. Mela- 
nin occurs in the tissues also, but here there is some doubt 
as to its origin. It is brownish black in color, occurs in fine 
grains, coarse particles, or in lumps; does not yield the reac- 
tion for iron, and is insoluble in acids, but is readily dissolved 
by ammonium sulphide. This should not be confused with 
hemosiderin, which is a chemic derivative of the hemoglobin 
of broken-down red blood-cells ; is yellowish in color ; responds 
to the reaction for iron; is insoluble in acids, alkalies, alcohol, 
and water, and exists especially extravascularly. It is regarded 
as a result of prolonged hemoglobinemia following severe or 
chronic infections. 

The general plan of distribution of melanin may be thus 
stated : In the blood current it may exist free or, more com- 
monly, is contained within the phagocytes and the red cells 
infected with pigmented parasites, and is more abundant in 
the capillaries than in the larger vessels. In the viscera it is 
oftenest seen in the spleen, bone-marrow, brain, and liver, 
especially in the endothelial cells, but in the spleen and bone- 
marrow it exists also outside the vessels and either between 
or within the cells proper to these tissues. 

The distribution of the parasites varies according to the 
type of the attack; it has been shown that the latter depends 
largely upon the localizations of the parasites. They are usu- 
ally abundant in the splenic blood irrespective of the form 
assumed by the attack. It occasionally happens that death 
supervenes, notwithstanding a progressive diminution of the 

174 



PLATE VI 



9 - | 










Fig. i. FiV. 2. 



lew w ^ 



<2> 




fw^^fe; ^H' : ' 



:: :^ 



I 






5; ife^ 



Fig- 3- 







Fig- 4- 



Fig. i. Liver in acute malaria. Fig. 2. Pia mater in acute malaria. Fig. 3. Spleen 
in acute malaria. Fig. 4. Omentum in acute malaria. (Kelsch and Kiener.) 



PATHOLOGIC ANATOMY I75 

parasites, so that the latter may be scanty or even absent. In 
the spleen are found not only schizonts, but also numerous 
sexual forms, which are likewise usually found in the bone- 
marrow and even in the liver, but in the brain gametes are 
conspicuously few. Parasitic development is checked almost 
immediately upon the death of the host. 

The spleen is always more or less enlarged, though perhaps 
slightly so in acute cases following recent infection. The edges 
are often rounded, the organ tending to lose its characteristic 
contour and to assume a spheric shape. The color varies 
from reddish brown to almost black, being darker in old 
malarials. In consistence it is usually softer than normal, 
often semifluid, sometimes resembling a bag of pulp. The 
capsule is thinned, occasionally adherent to the adjacent' 
organs, and is very liable to rupture. The cut surface is dark 
in proportion to the age of the infection. The pigmentation 
is occasionally uniform and the tissues hardly distinguishable, 
though, as a rule, the Malpighian bodies stand out distinctly. 
The venous sinuses are often dilated. Microscopically there 
is enormous cellular hyperplasia with distention of Mall's 
pulp cords. The spleen cells are everywhere intercalated with 
red blood corpuscles, a large per cent, of which are infected. 
The parasites may be in the same or in different stages of 
development. The pigment is contained in the large mono- 
nucleated leukocytes, endothelial cells, and giant cells. The 
latter contain also red cells, parasites, and even small phago- 
cytes, and are most abundant in the splenic vein. They some- 
times show evidences of necrosis. The Malpighian bodies 
and the fibrous trabecular are usually unpigmented. Mitotic 
cells may be found in the pulp and in the Malpighian bodies. 
The circulation may be so obstructed that edema, interstitial 
hemorrhage, and cellular necrosis may occur. 

The liver is generally enlarged, but in a less proportion as 
to frequency and size than the spleen. The color is usually 
a dirty brown, the surface is sleek, and the form is preserved. 
The consistence may be normal or somewhat diminished. The 
parenchyma presents a reddish-brown color after recent in- 
fection and the cut surface drips blood. The gall-bladder 



176 THE STUDY OF MALARIA 

is often distended with a quantity of dark, inspissated bile. 
Microscopically parasites are not so abundant as in the spleen. 
Pigment is found in the vessels, especially in the blood capil- 
laries. Here are found also altered parasites, melaniferous 
leukocytes, and large endothelial cells containing coarse grains 
of pigment. The macrophages are sometimes of an enormous 
size. The pigmented endothelial cells are swollen and the 
capillaries are not infrequently entirely obstructed with pig- 
mented cellular elements. The hepatic cells do not contain 
melanin, but are frequently charged with hemosiderin, and 
may show evidences of cloudy swelling, atrophy, or necrosis. 
Karyokinesis is occasionally noted. Areas of focal necrosis 
have been described. 

The kidneys on gross inspection show few changes; they 
may be slightly enlarged and hyperemia Microscopic exami- 
nation shows a marked pigmentation of the Malpighian cor- 
puscles, together with degenerated tubular epithelium. While 
the epithelium of the tubules may be healthy, it often shows 
cloudy swelling and necrosis. In the straight tubules there 
may be casts of various sorts. Melanin is found in the glome- 
ruli, less often in the tubules. The cells may contain hemo- 
siderin granules. Parasites are rare in the glomerular ves- 
sels, but may be found in the intertubular capillaries. 
Ewing's 177 case with massing of the parasites in the renal 
capillaries has been mentioned. A true glomerulitis has been 
found in cases of the algid type. 

In cerebral cases the only variation from the normal con- 
dition of the stomach and bowels may be a slight pigmen- 
tation. In fatal cases of the algid and choleraic forms the 
gastro-intestinal tract may contain a bloody fluid and the 
mucous membrane may be swollen, hyperemic, pigmented, 
necrotic, or ulcerated. The follicles and Peyer's patches may 
be hypertrophied and prominent. Microscopically there is 
vivid injection, parasitic and pigmentary thrombosis of the 
capillaries, hemorrhagic points, and necrosis. The peritoneum 
is usually normal. 

Macroscopically the lungs may show nothing abnormal save, 
probably, slight results of hypostasis, which in some cases may 



PATHOLOGIC ANATOMY 1 77 

be cadaveric lesions. Occasionally there are hemorrhagic 
areas. Microscopically neither pigment nor parasites are so 
evident as in certain of the other organs. The capillaries are 
congested, sometimes thrombosed, and contain infected ery- 
throcytes, phagocytes, which often show signs of degenera- 
tion, and macrophages. The capillary epithelium may be swol- 
len, but is only occasionally pigmented. The pleurae show 
nothing abnormal. 

The heart muscle is ordinarily pale and flabby, but the 
muscular fibers do not usually afford degenerative signs. The 
capillaries may contain parasites in greater or less number, and 
the endothelium may be swollen. Cases in which the parasites 
are very numerous in the cardiac capillaries, such as that of 
Ewing, 381 are very rare. 

In cerebral cases the meninges of the brain are deeply 
hyperemic, and excess of serum is found in the meshes of 
the pia, in the ventricles, and at the base of the brain. The 
cerebral substance is commonly darkly pigmented and con- 
gested, and may show hemorrhages, usually punctiform, occa- 
sionally larger. The hemorrhages occur oftener in the cere- 
brum, but may be present in the cerebellum. In the abdominal 
form the brain may show but few pathologic changes. Micro- 
scopically in the cerebral cases the capillaries are seen to be 
rilled, even to occlusion, with pigment, parasites, and phago- 
cytes, the latter in the same or in different stages of schizo- 
gony; gametes are seldom found. In some instances nearly 
every red cell contains one or more parasites. Localization of 
parasites are found not only in the cerebrum, but also in the 
cerebellum and medulla. The capillary endothelium may be 
swollen, pigmented, and undergoing fatty degeneration. Sec- 
ondary changes, such as perivascular exudation, hemorrhages, 
and necrosis, are not uncommon results of thrombosis. De- 
generative changes in the ganglion cells have been detected. 

The bone-marrow is of a dark color approaching that of 
the spleen, and sometimes diffluent. Microscopic examination 
reveals hyperemia, the capillaries being engorged with pig- 
mented parasites and giant cells clinging to the vessel walls. 
The parasites exist as free spores, schizonts, which are fre- 
12 



178 THE STUDY OF MALARIA 

quently speculating, and gametes in large numbers. Extra- 
vascular parasites and free pigment are also found. 

CHRONIC MALARIA 

The spleen is always enlarged. The form is usually pre- 
served. Its average weight is from 700 to 800 grams, though 
it may attain four or five times this weight. In consistence 
it is usually firmer than normal. The capsule is thickened, 
especially at the convexity. Upon the surface are scattered 
indurated whitish plaques of fibrous, occasionally calcareous, 
consistence, evidences of perisplenitis. Adhesions to the 
diaphragm or other parts are not infrequent. Subcapsular 
infarcts are occasionally encountered. In section the paren- 
chyma is usually found firm, only rarely is it of diminished 
consistence. The color varies from that of muscular tissue to 
slate color. The thickened trabecular, like white bands, are 
very evident. The Malpighian follicles are sometimes con- 
spicuous, sometimes indistinct. In old cases there is an over- 
growth of connective tissue, particularly near the capsule. His- 
tologically the chief changes found are trabecular hyperplasia 
and venous dilatation. The process sometimes resembles a 
hypertrophic cirrhosis. The fibrous trabeculse are hypertro- 
phied and there is formation of new connective tissue. The 
venules are notably dilated, the walls thickened, and the blood 
rich in pigmented leukocytes and macrophages. The deposition 
of pigment is in general similar to that in acute malaria. 
There is at times little change in the lymphoid tissue forming 
the arterial sheaths and Malpighian bodies, but this may be 
hyperplastic. Necrosis of the spleen pulp is observed, sur- 
rounded by evidences of regeneration. These regenerative 
processes consist chiefly of increased vascularization, forma- 
tion of connective-tissue network enclosing giant cells, and 
hyperplasia of lymphoid tissue beginning in the Malpighian 
bodies. 

The liver is not so constantly enlarged as is the spleen and 
never attains so excessive a degree of hypertrophy. It may 
weigh from 2 to 4 kilograms. In rare instances it is atrophic. 
The consistence is firm, occasionally somewhat doughy. The 



PLATE VII 






Si 



•^*— 



''£'■■ 




Figs. 1,2. Liver in 



Fig. 2. Fig. 3. 

chronic malaria. Fig. 3. Spleen in chronic malaria. (Kelsch 
and Kiener.) 



PATHOLOGIC ANATOMY 1 79 

capsule is tense and may be thickened. There may be present 
whitish bands or patches, the results of perihepatitis. The 
color varies from reddish to almost black. The cut surface 
is usually found to be congested and may drip with blood. The 
color is more or less dark red. There may sometimes be de- 
tected on gross inspection an increase of connective tissue. 
Microscopically the hepatic cells are seen to be hypertrophied 
and hyperplastic, showing evidences of cloudy swelling and 
necrosis, or atrophied as a consequence of vascular dilatation. 
In certain areas there may be a complete disappearance of 
hepatic cells, which are replaced by connective tissue, Kupffer's 
cells, or beginning formation of new hepatic cells. The nuclei 
are frequently multiple, and when single may be much larger 
than normal and contain one or two nucleoli. The hepatic 
cells may be charged with hemosiderin. . Pigment is contained 
in the endothelial and Kupffer's cells, especially in congested 
areas and in the periphery of the lobule. There is sometimes 
diffuse overgrowth of connective tissue. The blood capillaries 
are usually dilated and congested with blood rich in pigmented 
leukocytes; the circulation is commonly sluggish. The bile 
capillaries are ordinarily unaltered. The perivascular lymph 
channels may be dilated. Amyloid degeneration beginning 
apparently at the periphery of the lobules is not rare. 

The kidneys are usually increased in volume and in weight. 
The contracted kidney has been described in connection with 
malaria, but there is some doubt as to the etiologic relation- 
ship. The surface of the kidney is smooth, the color is dark 
red, and the consistence is slightly increased. Upon section 
the cortical substance is reddish gray. The pyramids are 
markedly hyperemic, the red tint being most decided at the 
border of the pyramidal substance. Upon microscopic ex- 
amination the convoluted tubules and ascending limb of 
Henle's loop are found dilated. The epithelium is swollen, 
charged with hemosiderin, and may be undergoing degenera- 
tion. In the collecting tubules the epithelium is, as a rule, only 
slightly altered. These tubules rarely contain granular or 
hyaline casts or desquamated epithelium. Bowman's capsule 
presents changes similar to those of the convoluted tubules. 



l8o THE STUDY OF MALARIA 

The renal arterioles are congested and the capillaries are dilated 
and gorged with blood rich in leukocytes, more marked in the 
pyramidal than in the cortical substance. Melanemia is not 
so decided in the kidney even when profuse in the spleen and 
liver. There is generally little change in the connective tissue. 
Here and there is a slight thickening of the intertubular con- 
nective tissue. The blood-vessels, the glomeruli, and the walls 
of the renal tubules may undergo amyloid degeneration. This 
is more diffuse in the kidneys in chronic malaria than in the 
other organs. 

The alimentary tract may show evidence of amyloid de- 
generation in the stomach or bowel and dysenteric lesions in 
the colon. 

In the lungs may be pigmentation and anemia, and in the 
pleural cavity an effusion. 

The heart is relaxed and often dilated and sometimes shows 
evidence of deg-eneration of the musculature. 

The bone-marrow is of firmer consistence and more deeply 
colored than normal, especially toward the ends of the long 
bones. There is usually a decrease of fat and a proliferation 
of marrow cells, together with large cells, some undergoing 
karyokinesis, lymphoid cells, and nucleated red cells. The 
vessel walls are thickened. In some instances there is atrophy 
of the bone-marrow. 

The elimination of the pigment probably consumes three 
or four months after the cessation of infection, though this 
varies with the activity of the eliminative processes. 

HEMOGLOBINURIC FEVER 

The pathologic findings vary in proportion to the proximity 
and intensity of the malarial attack. In addition to the changes 
characteristic of malaria there are found, in blackwater fever 
subjects, the results of hemoglobinemia and polycholia chiefly 
in the kidneys and liver. Occasionally post mortems do not 
reveal malarial evidences, as in two cases reported by Curry, 186 
but this is very exceptional. The body is usually deeply jaun- 
diced. There may or may not be edema. The muscular sys- 
tem is often icteric. 



PLATE VIII 




? J-^faffi £-11111 -s ' H 














'Vi',r .^ 



BMfl 



■»■*•.; ■'.., 






Fie. i. 







t|*45y 



















^KCBST,^.- ~--**- . 



Fig. 2. 



Fig. i. — The kidney in chronic malaria with hemoglobinuric fever. 
Fig. 2. — The kidney in malarias cachexia. (Kelsch and Kiener.) 



PATHOLOGIC ANATOMY l8l 

The spleen is enlarged, often enormously so, and congested. 
The surface color varies from grayish to reddish brown, almost 
black. The capsule is thickened and usually strips easily, but 
may be adherent. The consistence of the organ is often so 
diminished that it appears like a pulpy sac. The trabecular 
are thickened and fibrous ; the pulp is decidedly increased. The 
Malpighian corpuscles are usually hypertrophied, sometimes 
giving the appearance of sago spleen. Pigment is usually 
abundant. It is contained within the cells or lying between 
them. The cells of the Malpighian bodies show the greatest 
quantity and largest masses. The large mononuclear cells and 
giant cells are pigmented. The leukocytes lying external to 
the walls of the small veins may show more pigment than those 
scattered here and there throughout the pulp. The color of 
the pigment varies from yellow to almost black, and may con- 
sist of hemosiderin or melanin. The walls of the smaller 
vessels are thickened, and the lumen may be obliterated. The 
sinuses may be obliterated with pigmented and other cells. 
The endothelial cells may be proliferating, and often contain 
granules of pigment. Parasites and pigmented leukocytes may 
be present in the spleen when not discoverable in the general 
circulation. There may be round cell infiltration around the 
trabecular. 

The liver is enlarged, congested, and surcharged with bile. 
It varies in color from a decided yellow to a dark brown. The 
capsule is slightly adherent. The surface is usually smooth, 
but there may be subcapsular nodules from the size of a pin- 
head to that of a pea, which on section exude a thick, cheesy 
matter. There is abundant pigmentation, often rod-shaped, 
especially of the endothelial cells, macrophages, and leukocytes. 
The course of the capillaries may be well marked by the pig- 
ment contained in the endothelial cells and that between the 
wall and the adjacent liver cells. Both the yellow and black 
pigments are found, the former especially, in the liver cells. 
Pigmentation is often more pronounced in the center of the 
lobule. Thrombi of pigmented cells in the capillaries and sub- 
lobular veins occur, with cloudy swelling and fatty degenera- 
tion of liver cells. These retrogressive processes are in the 



l82 THE STUDY OF MALARIA 

form of islands. The biliary injection, more intense in the 
center of the hepatic lobule, may extend to the smallest 
branches. Regenerative efforts on the part of the liver cells 
are very much more common than in pernicious malaria (Mar- 
chiafava and Bignami). Karyokinetic barrels and manasters 
predominate. This is interpreted by Bastianelli as evidence 
of hyperfunction of the liver. Marchiafava and Bastianelli 
both agree in believing that this multiplication of the hepatic 
cells is an attempt on the part of the liver to meet the in- 
creased demands for work in eliminating the detritus of hemo- 
globin (Thayer). The gall-bladder is usually distended with 
bile. 

The kidneys are generally congested, weigh more, and are 
softer than normal. The capsule is loosely attached. On 
section the cortex is often yellowish ; the pyramids may present 
brownish streaks, more intense toward the apices. In the 
cortex may be found wedge-shaped hemorrhages with bases 
toward the capsule and apices pointing toward the medulla. 
The medullary pyramids may show minute hemorrhages. The 
glomeruli often escape undamaged; there is rarely any pig- 
mentation of the cells within Bowman's capsule ; there may be 
cloudy swelling, and slight epithelial desquamation. The 
epithelia of the convoluted tubules usually show cloudy swell- 
ing, fatty degeneration, or coagulation necrosis. There may be 
pigmentation of the epithelial cells. The lumina are often 
plugged with hemoglobin casts holding the epithelia in place. 
The changes in the straight tubules are similar, but casts are 
more numerous. The epithelium of Henle's loops is better 
preserved, but the lumen is usually choked with casts of hemo- 
globin and epithelial detritus from the convoluted tubules. 
Biliary pigment also occurs here. Karyokinesis is sometimes 
seen in the epithelium of Henle's loops and of the convoluted 
tubules. 

The stomach and intestines may be negative. The serous 
coat may be pale, the mucous membrane congested and bile- 
stained, especially near the opening of the common bile-duct. 
There may be isolated hemorrhages, excoriations, and pigmen- 
tation. The pancreas is normal. 



PLATE IX 




Fig. i. 



V\ 



! i» \ .'? 



*.-".*'- 



Jfc W 



Fig. 2. 
The kidneys in blackwater fever (Werner). 
Fig. i. — Occlusion of the straight tubules. 
Fig. 2. — Iron reaction with potassium ferrocyanide. 



PLATE X 




Fig. 2. 



The kidneys in blackwater fever (Werner). 
Fig. i. — Degenerative changes in the epithelium of the convoluted tubules. 
Fig. 2. — Dilatation of the lumen of the convoluted tubules. 



PLATE XI 




Fig. i. 




Fig. 2. 

The kidneys in blackwater fever (Werner). 

Fig. i. — Different characters of included masses in the glomeruli, the convoluted 

tubules, the straight tubules, and the intercalary portion. 
Fig. 2. — Different characters of coagula in the ascending and descending limbs 
of Henle's loops. 



PATHOLOGIC ANATOMY 1 83 

The pleurae may show punctate hemorrhages and the cavity 
may contain a quantity of serous fluid. The surface of the 
lungs may show slaty specks and striae. The cut surface is 
very pale, and exudes a very small amount of very pale, frothy, 
serous fluid. There may be an ashy discoloration in the course 
of the vessels, hypostatic congestion, and edema. 

The pericardium may contain from a few drams to several 
ounces of a clear or sanguineous fluid, and may present hemor- 
rhages varying in size from that of a millet seed to that of a 
cent. The heart is pale and often flabby. The muscular 
fibers are easily separable; the walls may be very thin. The 
left ventricle is usually strongly contracted, the right collapsed. 
Auricles and ventricles may contain coagula or thrombi. 
Microscopically the fibers stain well and show striations per- 
fectly; there are some areas of slight pigmentation and some 
of connective-tissue proliferation; the nerve trunks in the 
transverse section show marked degeneration; empty nerve 
sheaths are seen, and some connective-tissue proliferation into 
funiculus (Goltman and Krauss). 

The brain is usually pale and unpigmented; the latter ven- 
tricles may contain an excess of fluid. The convexity of the 
pia may show slight cloudiness in the course of the vessels. 
The puncta vasculosa may be scarcely visible. The bone- 
marrow shows the usual changes of malaria. Melanin, hemo- 
siderin, and proliferating normoblasts may be found. 



CHAPTER V 

CLINICAL HISTORY 

The simplest and most logic classification of the malarial 
fevers is, according to the form of the several parasites caus- 
ing them, into tertian, quartan, and estivo-autumnal. The en- 
deavor to affiliate the tertian and quartan parasites with the 
intermittent fevers and the estivo-autumnal with the remittent 
is fruitless, for a remittent temperature is by no means a 
characteristic of estivo-autumnal infections. Neither is the 
division into quotidian, tertian, and quartan consistent. Quoti- 
dian paroxysms may be due to estivo-autumnal infection, 
double tertian, or triple quartan. Tertian paroxysms may be 
produced by estivo-autumnal parasites or by simple tertian. 
The three forms of malaria will be studied in their acute and 
chronic courses, larvated or masked forms, with the complica- 
tions and sequelae. 

ACUTE MALARIA 

Incubation. — The period of incubation varies within very 
wide limits. It may be stated as a general proposition that the 
incubation period is longest in quartan infections and shortest 
in the estivo-autumnal. The average period is, for quartan, 
twelve to eighteen days; tertian, six to fourteen days, and 
estivo-autumnal, two to ten days. Much longer periods, run- 
ning into several months, have been reliably recorded. These 
must be regarded as cases of chronic malaria where the latent 
stage precedes the active, and are analogous to those cases of 
syphilis in which the secondary manifestations occur without 
recognized primary lesion, and are to be explained satisfactorily 
only by parthenogenesis. 

General Description of a Malarial Paroxysm. — The forms 
of acute malaria have so many points in common that it is 
convenient to describe first the typic malarial paroxysm. 

184 



CLINICAL HISTORY 1 85 

Prodomata may be perceived by the patient. They may 
correspond to the last few parasitic sporulations preceding that 
which causes the paroxysms or may occur only a few hours 
before the access. They are ill-defined, but usually consist of 
languor, anorexia, headache, aching of the loins and hips, 
thirst, epigastric distress, a disposition to stretch and yawn, 
and chilliness along the course of the spine. These symptoms 
may be so slight as to escape attention. The typic malarial 
paroxysm comprises three well-marked stages : the cold stage, 
the hot stage, and the sweating stage. 

The cold stag-e presents itself with the rapid intensification 
of the prodromata described. The sensation of coldness spreads 
to every part of the body. The skin becomes pale, especially 
the lips, the ears, and the nails, and the papillse of the skin 
stand out, forming the so-called "goose-skin." The patient 
shivers, sometimes so violently that he shakes the bed; he 
covers up, his teeth chatter, and he looks and feels cold. The 
slightest motion of the body or of the bedclothing increases 
the vehemence of these phenomena. Notwithstanding these 
evidences of coldness, the thermometer shows an elevation of 
internal temperature. The fever may even precede the cold 
stage. The patient complains of a tight headache, a backache, 
precordial oppression, and dyspnea. He often complains of 
general soreness, as severe as if having been beaten. He may 
suffer with nausea and vomiting of bile. There is apt to be 
frequent micturition of small quantities of limpid urine. The 
respiration is rapid and tremulous. The pulse is accelerated, 
diminished in volume, and increased in tension. The cold stage 
may last from a few minutes to two or three hours. 

With the onset of the hot stage hot flashes alternate with 
cold until, the sense of heat becoming general, the patient 
presents a very different picture from that of the first stage. 
He begins to uncover, the skin is flushed and hot, the pulse 
full and bounding, the respiration deeper, and the urine is 
scanty and high colored. There may be constipation or 
diarrhea. The tongue is coated, bulky, and usually shows 
indentations produced by the teeth. Herpes appears upon the 
lips or nose. The spleen is enlarged and the upper half of the 



i86 



THE STUDY OF MALARIA 



abdomen is tender on pressure. The headache, soreness, 
nausea, and vomiting continue, there is often great thirst and 
epigastric pain, and the temperature continues to rise. 

When the temperature is at its height the sweating stage is 
ushered in by crisis. Beads of perspiration begin to appear 
upon the face, then a universal sweat breaks out, and the skin, 
which was first cold and rough, then hot and dry, now becomes 
moist and natural. The temperature falls to normal, often a 
little below; the pulse and respiration resume their normal 



m 

< 
UJ 

a. 

UJ 

H 


m. oi. 

300 

290 
2S0 
270 
260 
250 
240 
230 
220 
210 
200 
190 
180 
170 
160 


DAY OF i 
DISEASE 1 






















DAY OP I 

MONTH jj 






















HOUR. 
























:ent. 
41°— 

40»— 

39»— 

3S«- 

37«- 

36°- 


FAH. 
106° 

105° 
104* 

103« 

( , 
102° 

101° 

100° 

99" 

98° 

970 

96* 














}. 


















t 


■ ; 




















: t 


" 




















1 






1" . 


'- J 




• 






| 


; 














. t 


























1 


ii 








['• 


i 












! 








I 


j 








•* 




Ik 


ti 






*r 


•<* 


-,'r 







































































Fig. 51. — Single tertian infection. 

features. The soreness disappears, the thirst ceases, and the 
patient often feels so comfortable that he takes a short nap. 

Such is the typic procession of one of the most remark- 
able events in the category of disease. The conspicuous 
changes, the swift succession of stages, and the punctual pe- 
riodicity of paroxysms are unparalleled in pathology. 

In some paroxysms, however, one or two stages may be 
missing. The temperature may rise unaccompanied by a cold 
stage or may fall to normal unattended by sweats. This con- 
stitutes the so-called dumb chill. The cold stage is the least 
constant, the hot stage the most so. The cold stage is most 



CLINICAL HISTORY 



l8 7 



constant in quartan fever, least so in estivo-autumnal infec- 
tions. 

Simple Tertian Infection. — Infection with a single brood 
of simple tertian parasites causes a paroxysm every other day. 
The parasites being in the same stage of development causes 
great regularity in the course. From the beginning of one 
paroxysm to the beginning of another is almost precisely forty- 
eight hours. When the interval is not quite so long, as some- 
times happens, the paroxysms are said to anticipate; when 



03 

H 

U) 

0. 

u 

H 


m. in. 

300 

290 
230 
270 
260 
250 
240 
230 
220 
210 
200 
190 
180 
170 
»69 


DAY OF 
DISEASE 




















DAY OP 
MONTH 




















HOUR. 




















;eni. 
41«~ 

400— 

39°— 

3S»- 

37«-- 

36«- 


FAH. 

106* 
105» 
104* 

103» 

(' 
102° 

101° 

100» 

99° 

98» 

970 

%o 












































































il 


1 


! 














f 






















1 l 


If 




: 






i\ 


J 




H 






h 








fe- 


!: 


V 






w. 


\t 


-r 
























j 


















• 








• 







Fig. 52. — Double tertian infection. 

longer, as is more rarely the case, they are said to postpone or 
to retard. Postponing is usually regarded as evidence of abat- 
ing activity. 

In more than half the simple tertian cases the infection is 
double ; that is, there are two distinct generations of parasites. 
These generally mature on alternate days; two paroxysms on 
one day with an intervening day of apyrexia being extremely 
rare. The paroxysms may occur at the same time every day 
and be similar in every respect. Usually, however, there is a 
perceptible difference between the paroxysms of successive 
days, a difference consisting of time of onset, severity, and 



i88 



THE STUDY OF MALARIA 



relative length of the stages of the paroxysms. It very rarely 
happens that the paroxysms are so lengthened, and one so 
anticipates that its onset occurs during the latter stage of the 
preceding paroxysm. They are styled subintrant attacks. 

A change of type from quotidian to tertian paroxysms, or 
vice versa, is commonly observed. The change from quotidian 
to tertian may be spontaneous or the result of incomplete medi- 
cation or improvement in hygienic conditions, one group of 
parasites perishing. A change from tertian to quotidian may 




Fig- 53- — Single quartan infection. 

occur without apparent cause or following indiscretions of 
various sorts. 

The onset is probably more common during the morning, 
but this is neither constant nor of diagnostic dignity. The 
invasion is almost always with a chill. The temperature rises 
suddenly and falls likewise. Commonly there are no grave 
symptoms, but a mild delirium is not rare. The temperature 
usually goes as high as 103° to 105° F. The average duration 
of the paroxysm is from eight to twelve hours. 

During apyrexia the patient may feel perfectly well except 
slight weakness, headache, or vertigo. He is usually able to 



CLINICAL HISTORY 



189 



attend to his duties. The tendency to spontaneous cure is 
greater than in either of the other forms of malaria, the attack 
not infrequently subsiding after a number of paroxysms, with- 
out any medication or with only a purgative. 

Quartan Infection. — The quartan parasite accomplishes its 
endogenous cycle in seventy-two hours. Hence infection with 
a single generation of quartan parasites produces a paroxysm 
followed by two days of apyrexia and a second paroxysm on 
the fourth day. Such attacks are popularly known in the South 
as "third-day chills." A double quartan infection reverses the 




Fig. 54. — Double quartan infection. 

course, causing two paroxysms on successive days, followed 
by a day of apyrexia. Triple quartan infections, the parasites 
maturing on successive days, give rise to quotidian fever. As 
in simple tertian intermittents, quartan accesses sometimes 
anticipate or retard. Subintrance in triple infections is rarely 
seen, due probably to the shorter duration of the paroxysms. 
Changes of type between single, double, and triple quartan are 
sometimes observed. 

The onset, especially in single infections, occurs probably 
more often during the afternoon hours. The symptoms are 



190 



THE STUDY OF MALARIA 



those of the typic paroxysm and are well marked. The cold 
stage is not only more constant than in the other forms, but is 
more intense and usually of longer duration. The three stages 
are sharply contrasted. Pernicious symptoms are very rarely 
observed in connection with quartan infections. This may be 
accounted for by the more equal distribution through the circu- 
lation of the parasites which show no tendency to congregate, 
and by the longer apyrexial periods between the paroxysms. 
The average duration of the paroxysm is eight or ten hours. 




Fig- 55- — Triple quartan infection. 

The obstinate disposition of quartan fever to recur has been 
a matter of common knowledge for centuries, and is still a 
popular idea. This may doubtless be accounted for at this day 
by the probability that, owing to the greater interval between 
the accesses, the specific is not properly taken. Most physicians 
will agree that quartan fever is just as amenable to appropriate 
therapy as the other acute forms. As in tertian fever, an 
almost complete feeling of well being may be experienced be- 
tween paroxysms, the patient usually being able to attend to 
business. 

Estivo-autumnal Infection. — The chief feature of infec- 



CLINICAL HISTORY 



I 9 I 



tion with estivo-autumnal parasites is the irregularity of the 
course as contrasted with that of tertian and quartan infec- 
tions. A classification is difficult and, while that into estivo- 
autumnal or malignant tertian and quotidian is perhaps best, 
these may be clinically indistinguishable. 

Malignant Tertian. — This form of infection is due to para- 
sites which tend to mature in forty-eight hours. It is character- 
ized by a long paroxysm and a short apyrexia. The duration 
of the access is from twenty-four to forty-eight hours or more. 



Ul 

a? 

H 
< 

W 

a. 
m 


tn»-ro. 

300 

290 
280 
270 
260 
250 
240 
230 
220 
210 
2oo 

190 
180 
170 
160 


OAY OP 
DISEASE 


























OAVOP 
MONTH 


























HOUR. 


























:ent. 
«•— 

40»— 

39»— 

38°- 

37»- 
36»_ 


TAH. 

106° 
10S» 
104* 
103» 
102° 
101° 
1Q0» 
990 

98» 
970 
96° 






















































s 








■ft 














] 


J 


i 


i 


















I 


I 




( 




















j 




1. 




\ 


: 












I 


: 






j 


i 


































: 


L - 


':■ 




k 


T- 








V s 


r 


i- 


f- 
































































: 











Fig. 56. — Tertian estivo-autumnal malaria. 

Anticipation and subintrance are oftener observed here than 
in any other form of malaria. 

Prodromal symptoms are usually pronounced. The cold 
stage is often not manifest; the sweating stage is less com- 
monly missing. The typic temperature is characteristic. It 
rises abruptly, often as high as 104° F. On reaching its 
height it remits with slight oscillations for a few hours. It 
then makes a marked remission and again rises suddenly, usu- 
ally higher than before. The final fall is by crisis. It is cus- 
tomary, following Marchiafava and Bignami, to divide this 
course into five stages : 1, the rise of invasion; 2, the fastigium; 



192 



THE STUDY OF MALARIA 



3, the pseudocrisis ; 4, the precritical rise; 5, the crisis. This 
curve is simulated only by simple tertian fever with subintrant 
attacks, which is uncommon. Unfortunately this typic 
sequence is far from constant; the modifications are very 
numerous and are too irregular to analyze. 

The symptoms of the hot stage are more pronounced than in 
the infections previously described. The headache and back- 
ache are worse, the general depression is more profound, stupor 
and delirium may appear, and pernicious symptoms may arise. 
During the short interval the patient does not regain his ease 




57. — Quotidian estivo-autumnal malar 



as in the simple intermittent fevers, but the aching and pros- 
tration continue, and he may be unaware that the fever has 
left. 

Quotidian. — The quotidian estivo-autumnal fever is more 
regular in its course than the tertian, especially at first, though 
there is nothing characteristic in the temperature curve, which 
may closely resemble a double tertian or a triple quartan. 
Later it is apt to lose some of its regularity by anticipation 
or by lengthening of the paroxysms, whose average duration 
is from six to ten hours. The chill is rather more constant 



CLINICAL HISTORY I93 

than in the tertian, otherwise the symptoms are identical, the 
patient not regaining strength from one paroxysm to another. 
In the interval the temperature is prone to sink, even as low 
as to 95° F. 

Mixed Infections. — Infections with two or more species of 
the malarial parasite are known as mixed or combined infec- 
tions. The most frequent combination is of simple tertian 
and estivo-autumnal. As a rule, one parasitic form predomi- 
nates and produces its usual picture; this may, however, be 
considerably modified by the other group of parasites. The 
most frequent modification in the temperature chart is a tend- 
ency to continuity. The paroxysms are not usually as typic 
as in simple infections and are not so regular in their occur- 
rence. 

Analysis of Symptoms. — Temperature. — The main char- 
acteristics of malarial temperature have been given when treat- 
ing of the several forms. It remains only to consider a few 
general traits. 

The feature of the temperature in uncomplicated and un- 
treated malaria is periodicity. The temperature is, in a great 
majority of instances, intermittent. The fever of longest 
intervals, the quartan, has only one mode of causation, the 
quartan parasite. The fever of next longest intervals between 
times of onset, the tertian, has two modes, the simple tertian 
parasites and the tertian estivo-autumnal ; while the fever of 
shortest intervals, the quotidian, may be due to triple quartan, 
double tertian, or quotidian estivo-autumnal infection. As 
intimated, quotidian fever may change to a single or double 
quartan or to a tertian, and both tertian and quartan may 
become quotidian, but tertian fever never becomes quartan, or 
vice versa, without reinfection. 

In tertian and quartan infections the temperature usually 
rises rapidly after the onset, reaching the acme during the 
second stage of the paroxysm and declining during the third 
to normal or a little below normal. This is also the usual 
course in quotidian estivo-autumnal, the temperature chart 
showing symmetric ascent and descent, producing an arrow- 
head appearance. In this infection the temperature descends 
13 



194 THE STUDY OF MALARIA 

rather lower during the fever-free interval than in the others. 
The typic run of tertian estivo-autumnal has been given as 
follows: i, the stage of initial ascent; 2, the fastigium, during 
which the temperature may show fluctuations of a half degree 
to a degree; 3, the pseudocrisis ; 4, the precritical or final 
ascent; and, 5, the crisis. 

Continued temperature in malaria is not as common as usu- 
ally regarded; remittent fever was formally thought to be the 
rule in the summer-autumn malarial fevers. The causes of 
this error are three ; first, in tertian estivo-autumnal infections 
the apyretic interval is short; secondly, this interval often 
occurs during the night or early morning hours; thirdly, the 
patient, guided by the discomfort which continues during the 
interval usually denies that he has been free from fever. 
Nevertheless, a continued temperature is occasionally noted 
in malaria, especially in tertian estivo-autumnal infections. It 
may be regularly remittent or may be irregular. The follow- 
ing are the chief causes of a continued malarial temperature : 

1. Prolongation of the paroxysms. 

2. Anticipation of the paroxysms. 

3. Infection with more than one brood of the same species 
of parasite. 

4. Infection with more than one species. 

5. Complications. 

So-called spontaneous recovery may occur in either form of 
malaria. As a rule, the recovery is only temporary and is 
merely the transition from the active to the latent stage, re- 
lapses usually occurring sooner or later. Favorable hygienic 
conditions encourage spontaneous cure. 

The duration of untreated acute malaria is too indefinite 
to permit of exact statements. While simple tertian may 
terminate after a few paroxysms, an estivo-autumnal fever 
may continue three or four weeks if it does not in the mean- 
time become pernicious. 

A postmalarial secondary fever, or spodogenous fever, is 
occasionally observed after the infection, particularly estivo- 
autumnal, has lasted for some time. It persists for days or 
weeks uninfluenced by quinine. The blood examination is 



CLINICAL HISTORY 195 

negative for parasites. . Resorption of debris, toxins, and vis- 
ceral lesions have been offered as explanations of this process, 
but none of these are entirely satisfactory. 

Circulatory System. — The Blood. — The blood, being the 
habitat of the parasites, furnishing their pabulum, containing 
their toxin, besides carrying one of the host's mechanism of 
defense against their depredations, shows important changes. 

The volume of the blood as a whole is somewhat diminished. 
The specific gravity is only slightly lowered, and usually only 
in recent infections, the destruction of the solid elements being 
nearly compensated by the excretion of fluids. The density, 
at first lowered, approaches normal as the infection persists. 
The experiments that have been performed with reference to 
the tonicity of the blood in malaria have uniformly shown 
that this is increased. . 

The parasites of malaria have a very unequal distribution, 
some being almost constantly found in the superficial circula- 
tion throughout their asexual cycle, others only during the 
early stages of their development, modestly retiring to the 
recesses of the viscera for procreation. The organisms are 
sometimes scanty in the peripheral blood, occasionally entirely 
absent. 

The tertian parasite, more abundant in the deep circulation, 
may be observed in the peripheral circulation throughout the 
course of the asexual cycle, excepting the sporulating forms, 
which are only exceptionally seen. The gametes are not in- 
frequently detected. 

The quartan parasite is most evenly distributed, being about 
equally common in the visceral and superficial blood. Fur- 
thermore, all stages of the asexual development, including 
the sporulating forms, may be followed in blood obtained 
from the peripheral circulation. Quartan gametes are rarely 
seen. 

The estivo-autumnal parasites are seen in only the earliest 
phases. In some localities the gametes are very commonly ob- 
served after the infection has persisted a week or more; in 
others, even where severe infections of long standing are en- 
countered, they are more rarely noted. 



196 THE STUDY OF MALARIA 

Pigment is most frequently contained within the large mono- 
nuclear, less often the polymorphonuclear, leukocytes, but may 
exist free in the blood current. It is of a dark reddish-brown 
or black color, and occurs as granules, rodlets, or irregular 
clumps. 

One of the best-known facts in the study of malaria is the 
rapid and widespread destruction of the red blood-cells. A 
certain number of erythrocytes perish with each parasitic 
sporulation like soldiers after a volley from the enemy. It is 
not uncommon for a fourth to a half million red cells per 
cmm. to be destroyed during each of the first two or three 
paroxysms, and this may progress until the count is consider- 
ably less than one million per cmm. As a rule, in uncompli- 
cated benign malaria this erythrorrhexis is greater during the 
early paroxysms, diminishing with each successive paroxysm, 
the cells apparently requiring some sort of immunity. It is 
likewise usual for the marked early destruction to be rapidly 
compensated, or nearly so, by the activity of the blood-forming 
organs. Later it is more difficult for these organs to replace 
even the smaller number of destroyed cells. Hence the anemia 
is commonly in proportion to the severity and duration of the 
attack. Restitution of the red cells is more rapid and certain 
with tertian and quartan than with estivo-autumnal infections. 
Race, age, and constitution are also factors in the rapidity of 
reconstruction. 

There are certain changes that occur in the infected cells 
which should be mentioned. The cells containing the simple 
tertian parasites are swollen and somewhat decolorized. Those 
containing the quartan parasites are shrunken and somewhat 
darker in color. The cells harboring estivo-autumnal organ- 
isms have the appearance of old gold or of brass, and become 
somewhat smaller. A curious appearance of some infected 
cells is what has been termed stippling-. This may be seen in 
both simple tertian and estivo-autumnal infections, but presents 
features more or less characteristic in each. In simple tertian 
the dots are fine and abundant. In estivo-autumnal they are 
coarse, irregular, maybe cleft-like, and few in number — from 
two to six. The fine stippling of tertian infection is also 



CLINICAL HISTORY 1 97 

known as "Schiiffner's dots." Stippling is brought out by- 
staining. 

A mysterious property of infected cells is their apparent 
tendency to mutual attraction. For instance, it is very common 
to observe under the microscope two or more infected cells in 
juxtaposition, even where these are the only infected cells in 
the field. This property, whatever be its nature, probably 
explains the parasitic localizations in pernicious attacks. 

Changes occur also in non-infected cells. The commonest 
of these are, in my experience, in the order named: the occur- 
rence of macrocytes and microcytes, polychromatophiles, and 
poikilocytes. Nucleated reds are occasionally observed. Baso- 
phile granulation is sometimes noted. It was this lesion which 
Plehn formerly mistook for the latent phase of the parasite. 
These granules appear in a varying number of cells, occa- 
sionally in those containing parasites, as minute dots or streaks 
from one-quarter to one-half micron in diameter. When few 
in number they appear coarser. They stain best with the 
Romanowsky class of stains. Basophile granulation is not 
characteristic of malaria, but is found in a number of affec- 
tions. Retraction of hemoglobin and vacuolization are com- 
mon findings in malarial blood. 

The hemoglobin generally falls decidedly. Its curve is apt 
to run parallel with and a little below that of the red cells, and 
is slower in returning to normal. The hemoglobin content is 
no guide as to the severity of the disease. 

The leukocytes are, in benign malaria, usually slightly dimin- 
ished. A leukocytosis is found only in pernicious malaria or 
in association with complications. The differential formula is 
the most noteworthy feature. Its peculiarity is the large 
mononuclear increase. Bastianelli 233 observed a diminution of 
the polymorphonuclears and increase of the large mono- 
nuclears, especially in advanced and pernicious cases, and less 
marked during the early paroxysms. Billings 280 noted a great 
absolute and relative increase of the large mononuclears, a 
decided diminution, both relatively and absolutely, of the poly- 
morphonuclears, a wide variation of small mononuclears, and 
a slight diminution of eosinophiles. Stephens and Christo- 



I98 THE STUDY OF MALARIA 

phers 57 have recorded that there is no increase of the large 
mononuclears during pyrexia, but that the increase is pro- 
nounced in the apyretic interval, or immediately following the 
rise of temperature, if only one such occurs. They also noted 
that in certain cases this change was extraordinarily marked, 
the large mononuclears during the interval even exceeding in 
number the polymorphonuclears. They observed further that 
in some cases the mononuclear increase was to be detected even 
during the fever stage, but in these cases it was still further 
evident during the interval. Rogers 44 concludes that the mono- 
nuclear increase is decidedly more marked and frequent in 
benign than in malignant tertians. He accounts for this by 
the shorter apyretic interval of the latter. Krauss 281 believes 
that it is not so much the absolute increase of the large mono- 
nuclear elements as the relative increase over the small lympho- 
cytes, which is characteristic of malaria. Ziemann 48 states that 
in the beginning of the access there is often a transient poly- 
morphonuclear leukocytosis, which recedes during the acme of 
the fever simultaneous with a relative increase of the large 
mononuclears, which may reach 15 per cent, or more. 

Eosinophilia, in the writer's experience, denotes complica- 
tions, ordinarily intestinal helminthiasis. 

Billings' 280 16 cases showed the following average: 

Per cent. 

Small mononuclears 16.9 

Large mononuclears 16.9 

Polymorphonuclears 65.04 

Eosinophils 0.96 

Krauss' 281 204 cases : 

Per cent. 

Small lymphocytes 14.8 

Large lymphocytes 19.5 

Polymorphonuclears 63.7 

Eosinophils 2.0 

Rogers 44 found that the large mononuclear leukocytes num- 
bered : 

0-8 per cent, in 6 cases 

8-12 per cent, in 10 cases 

12-15 P<?r cent, in 25 cases 

15-20 per cent, in 16 cases 

Over 20 per cent, in 20 cases 



CLINICAL HISTORY 1 99 

The leukocytes occasionally undergo degenerative changes, 
among which are fatty degeneration and vacuolization of the 
protoplasm and fragmentation and chromatolysis of the 
nucleus. 

The blood platelets are somewhat increased in malaria, espe- 
cially during the interval following a severe attack. 

The carefully conducted experiments of Capograssi 84 tend 
to show that, while malarial blood possesses agglutinative 
properties, it is of no diagnostic importance. 

Celli, Carducci, and Casagrandi, 147 investigating together, 
were unable to determine definitely the existence of an hemo- 
lysin, but concluded that such a body probably existed. Later 
Casagrandi was able to verify the presence of an hemolysin 
in malarial blood, and concluded that it was masked by an 
antibody. De Blasi 82 found in a watery solution of centrifu- 
gated red cells antihemolytic action in 15 cases out of 19. The 
4 negative cases were in chronic malarias who had been 
under the influence of quinine a long time. This hemolytic 
action is not specific for malaria, occurring in measles, typhus, 
erysipelas, and scarlatina, but not in healthy persons. 

At the height of the fever the pulse may reach 130 or 
more. During the interval it usually becomes almost quite 
normal in tertian and quartan infections. In estivo-autumnal 
fever it depends upon the severity of the attack and the resist- 
ance of the patient. Occasionally the rapidity of the pulse does 
not show the usual relation to the height of the temperature, 
but may be below 100, with high fever. This is sometimes 
observed during the attack, but is rather more common during 
convalescence. During the cold stage of the paroxysm the 
blood pressure rises decidedly, falling during the second stage, 
to become normal in the sweating stage. This is fairly con- 
stant, variations being due not to a difference of parasites, 
but to individual conditions. An anemic murmur may be heard 
over the heart. A sense of precordial oppression or acute pain 
are common complaints. 

Respiratory Organs. — Respiration is usually accelerated in 
proportion to the temperature. Cough is a frequent symptom. 
In children a frequently repeated superficial hacking cough is 



200 THE STUDY OF MALARIA 

often an indication of nausea. Bronchial catarrh is not infre- 
quently observed, accompanied by sibilant rales on ausculta- 
tion. Epistaxis may occur and is occasionally alarmingly pro- 
fuse. 

Gastro-intestinal Organs. — While the paroxysm is on, the 
appetite is usually completely lost. In tertian and quartan 
malaria this may be regained during the interval, but in estivo- 
autumnal anorexia generally persists throughout apyrexia. The 
patient ordinarily complains of a bitter taste in the mouth and 
fulness, discomfort, or pain in the epigastric region. The 
tongue is large, flabby, thickly coated, usually anemic, and 
showing the prints of the teeth along the edges. Nausea is 
nearly a constant symptom, and retching and vomiting are dis- 
tressing. The vomitus consists of matters ingested, bile, or 
slimy mucus. The bowels are constipated, regular, or loose, in 
the order of frequency named; choleraic or dysenteric dis- 
charges occasionally appear. More or less enlargement of the 
spleen is a usual occurrence, together with pain and tenderness 
in the left hypochondrium. In primary acute infections the 
enlargement may not be prominent; in later infections the 
spleen is often palpable beyond the costal margin. The spleen 
is rarely much enlarged in the negro. Enlargement of the liver 
is much less constant and less marked than splenic hypertrophy. 
There usually exists tenderness in the epigastric and right 
hypochondriac regions. 

Genito-urinary Organs. — Urine. — As a general rule, the 
urine emitted during a cold stage is paler in color and that of 
the stage of fever highly colored, but individual circumstances 
may produce numerous exceptions to this rule. In certain 
cases of estivo-autumnal fever the urine may be very highly 
colored and contain a heavy deposit. In these cases the urine 
contains biliary coloring matters and an excess of urobilin. 
The diazo reaction sometimes obtains. The indican is fre- 
quently increased. In tertian and quartan cases the quantity 
of the urine is somewhat augmented, in estivo-autumnal dimin- 
ished. Polyuria of tertian and quartan malaria and that occur- 
ring sometimes in estivo-autumnal occurs under two conditions, 
the polyuria of the paroxysm and that of convalescence or post- 



CLINICAL HISTORY 201 

malarial polyuria. In the former case the increase in the quan- 
tity of urine excreted coincides nearly with the paroxysm, the 
amount diminishing during the interval. The polyuria of 
convalescence ordinarily begins from three to six days after 
the attack and continues for a few days to several weeks. The 
reaction is acid, varying directly with the concentration of the 
urine. The specific gravity does not always bear a definite 
relation to the amount of the urine, as might be inferred, but 
may be relatively high when the urine is abundant, or low with 
scanty urine. 

The output of urea is increased. The increase begins sev- 
eral hours before the attack, attains its maximum toward the 
end of the cold stage, declining to or below normal at the end 
of the paroxysm. A curious fact noted by Ringer and by 
Senator 227 is that when the return of the attack has been pre- 
vented by the administration of quinine, there is still to be 
observed an increase in the excretion of urea on the days upon 
which the paroxysm should have occurred. 

The uric acid content of the urine is only slightly, if at all, 
modified. The amount of chlorides runs parallel with the 
quantity of urine. The phosphates are eliminated in quantities 
less than normal during the fever, and in greater quantities 
during apyrexia. The entire twenty-four-hour urine com- 
monly shows an increase. The variations in the excretion of 
the sulphates are similar to those in regard to urea. 

The elimination of the sodium and potassium bases is very 
inconstant, both as to quantity and as to the stage of the disease 
during which elimination takes place. Malarial urine contains 
an excess of iron, especially after the paroxysm. It is de- 
pendent upon and proportionate to the destruction of erythro- 
cytes. 

The occurrence of albumin in the urine is relatively infre- 
quent in the mild attacks of simple intermittent which ter- 
minate after one or two paroxysms. In severe estivo-autumnal 
infections, however, it is exceedingly frequent. Its frequency 
varies not only with the type and severity of the attack, but 
also with locality and other circumstances. The following 
reports are tabulated to show the extent of these differences, 



202 THE STUDY OF MALARIA 

the denominator indicating the number of cases of malaria, 
the numerator the number in which albumin was found : 

^.OStcl * Tq-J 

F. Plehn 5 T |j. 

Marchoux 96 ft 

Borne 60 3.8% 

" Thayer and Hewetson" 9 iff 

Solon 86 25% 

Schoo 90 2% 

Thayer 282 ffl 

Anders 283 T }U 

Atkinson 285 xVx 

Chamberlain 43 xfir 

Frerichs 61 If 

Cook 285 tW 

Marchiafava and Bignami 22 say that albuminuria is rare in 
their experience, though Kelsch and Kiener 178 hold the opposite 
view, and Craig 70 states that it occurs in a majority of the 
severe cases. 

An increased toxicity of the urine has been found in large 
per cent, of cases of malaria, greatest during apyrexia and usu- 
ally intensifying with each successive paroxysm. Brousse 86 
arrived at the following conclusions : 1. The urotoxic coefficient, 
calculated by means of the formula of Bouchard, the average 
coefficient being .464, rises during the attack, and the physio- 
logic effects observed are those usually noted after the injec- 
tion of urine; dyspnea, miosis, fall of temperature, exophthal- 
mia, besides convulsions. 2. This toxicity is diminished during 
the period of convalescence from the intermittent fevers very 
much below that of the urine during the access, and, further- 
more, more feeble than that of normal urine. 

Nervous System. — Headache is one of the most invariable 
symptoms of malaria. Backache and somatic soreness are 
severe. Sometimes hyperesthesia is seen. Vertigo is the rule, 
especially when the patient is upright. Neuralgia, facial or 
intercostal, is a not infrequent symptom. Stupor and delirium 
are present in grave cases, particularly in children. 

Skin. — During the first stage of the paroxysm the skin is 
blanched and cold, during the second stage hot, dry, and per- 
haps turgid, during the third bathed with sweat, becoming 
natural toward apyrexia. Icterus is not a pronounced symptom 



CLINICAL HISTORY 203 

in acute cases except in certain pernicious forms. With the 
possible exception of pneumonia herpes is seen more frequently 
in malaria than in any other disease. Its commonest sites are 
the lips and nose, but it may appear elsewhere. It is not nearly 
so common in the negro as in the white. Urticaria and 
erythema are sometimes observed. 

PERNICIOUS MALARIA 

Malaria threatens or destroys life through its inherent dan- 
gers, acutely expressed, through the sequelae of chronic mani- 
festations, or through complications in any stage. Pernicious 
malaria is that form of malaria, extremely acute, which, inde- 
pendently of complications, endangers life in a few hours or 
a few days. This gravity may be due to the intensification of 
ordinary malarial symptoms or to the advent of unusual ones. 
It should be clearly understood that pernicious fever is not a 
pathologic entity, but is a form of malaria from the simple 
modes of which it sometimes differs only in degree. Its patho- 
genesis is intimately associated with the life history of the 
malarial parasite, much more so than is hemoglobinuric fever. 
Intermediate forms may be encountered which may be difficult 
to place, as cases with slight somnolence, abundant sweats, or 
cold surface. 

Though the pernicious forms of malaria were alluded to 
by Hippocrates and by Celsus, they did not receive any de- 
tailed consideration until 1743, when Torti described them. 
This pyretologist divided the pernicious fevers into solitaries, 
those characterized by the continuity or acuteness of the ordi- 
nary symptoms, and the comitates, in which one grave symptom 
predominated. The comitate? he subdivided into the colliqua- 
tive, including the choleraic, dysenteric, atrabiliary, cardialgic, 
and diaphoretic, and the coagulative, including the syncopal, 
algid, and lethargic forms. 

Alibert, in 1804, distinguished twenty varieties of pernicious 
malaria. 

Roux, following Jaccoud's classification, looks on all as 
originating in the vasomotor and sympathetic systems or in 
the cerebrospinal system. 



204 THE STUDY OF MALARIA 

Kelsch and Kiener adopt Torti's system with slight modifica- 
tions. 

Marchiafava and Bignami arrange the pernicious forms, ac- 
cording to the course of temperature, into tertian, quotidian, 
subcontinuous, and larval. 

Manson groups them roughly into cerebral — including the 
hyperpyrexia!, comatose, convulsive, and paretic forms — and 
algid, including the syncopal, choleriform, dysenteric, and 
hemoglobinuric forms. 

Dantec classifies the varieties anatomically according to the 
organs which bear the brunt of the attack, namely : ( i ) The 
brain, (2) the medulla, (3) the spinal cord, (4) the heart, (5) 
the lungs, and (6) the digestive tube. 

Homem describes fifteen definite forms, besides several un- 
defined varieties. 

Cardamatis distinguishes seventeen varieties. 

More than thirty so-called varieties of pernicious malaria 
have been described. A partial list of these includes the apo- 
plectic, ataxic, comatose, sudoral or diaphoretic, delirious, 
eclamptic or convulsive, tetanic, typhoid, amaurotic, aphasic, 
ardent, exanthematous, hemiplegic, hydrophobic, neuralgic, 
cerebromeningeal, cardialgic, dyspenic or asthmatic, pneumo- 
nic, pleuritic, syncopal, hemoptoic, algid, choleraic, dysenteric, 
gastric or gastralgic, hemorrhagic, bilious or hepatic, lymphatic, 
rheumatic, and nephritic forms. 

This multiplicity is due to two causes : first, the fanciful and 
unnecessary subdivision of typic forms ; second, the mistaking 
of complications for true pernicious attacks. 

Any classification is not absolutely essential, and all are more 
or less arbitrary. Nevertheless, for convenience, all forms of 
true pernicious malaria may be easily and logically arranged 
into (1) cerebrospinal, (2) thoracic, and (3) abdominal forms. 

Cerebrospinal Forms. — The representative type of cerebro- 
spinal pernicious malaria is the comatose variety, which is, as 
well, the most frequent of all varieties. 

Comatose malaria may make its appearance as the first mani- 
festation of malaria or, more commonly, after the lapse of 
one or more paroxysms, typic or irregular. Violent head- 



CLINICAL HISTORY 



205 



ache, stupid countenence, and somnolence, interrupted by fre- 
quent sighing, with a mild grade of mental aberration and de- 
fective articulation and vision, are not uncommon prodomata. 
These may, however, be so slight as to escape notice. The 
onset of cerebral symptoms may be with violent abruptness 
(the apoplectic form of some writers) or, as is most common, 
begins within a few hours after the commencement of the 
paroxysm with somnolence, which gradually deepens into 





■ . ; ; | . : ; : • ! :-: , | 1 j II | II 1 1 1 j H+j+H j |||| 1 1 1 1 j | [ \ i \ ] \ j j 1 ;rt| 1 1 111 lj 1 | |llj]]]l[||| 


ft* 

toe 

"f 

10% 
10% 






ffljftTtffto"! 1 ! 1 ! i 1 1 - 

1 jl '! irfH"" 


i'l 

loo 

11 
tf 

11 

% 




hi illffflriTiii Tn" fll mmtt r 1 lltirn 1 ft 


lll^i 



Fig. 58. — Comatose malaria ; recovery. 

stupor and coma. It has occasionally happened that malarial 
coma has come on during natural sleep, the condition of the 
patient being discovered by accident. Convulsions may precede 
the coma, especially in children, or there may be extreme rest- 
lessness, gritting the teeth, and jactitation. The cerebral symp- 
toms may vary from the marked drowsiness to profoundest 
coma. The eyes may be closed or open (coma-vigil). The 
pupils are usually equal and dilated or contracted, but may be 



206 THE STUDY OF MALARIA 

unequal and may or may not react to light. Strabismus is an 
occasional symptom. The face is congested in individuals re- 
cently attacked or pallid in older sufferers. The skin is at 
first hot and dry, perhaps slightly jaundiced; later it may be 
bathed with sweat. Petechias are occasionally seen. Trismus 
may be present, but the extremities are usually completely re- 
laxed, though sensation and motion are often not entirely abol- 
ished, as sometimes evidenced by resistence to hypodermic 
medication. Cases manifesting muscular rigidity and tonic 
contractures have been reported by Schellong 92 and by 
Brown. 286 Hyperesthesia and muscular tremors are not infre- 
quently present. The reflexes may be increased or diminished. 

There may be twitching of the muscles of the face, usually 
confined to one side. Loud calls may not elicit response, and 
shaking only groans and unintelligible utterances. The coma 
may be intermittent, running parallel with the temperature. 
The fever in most cases varies from ioi° to 103° F., but 
may be subnormal or hyperpyrexial. The pulse is at first 
full and bounding, later small, rapid, and feeble. Dilation 
of the right side of the heart may exist and an anemic mur- 
mur may sometimes be heard. The respiration may be quiet, 
slow or rapid, or blowing and stertorous, with Cheyne-Stokes 
characteristics late in the course. Edema of the lungs is an 
occasional late occurrence. Nausea and vomiting are seen 
early in the attack, if they are present at all. The mouth 
and tongue are dry, the latter deeply coated. Herpes and 
sordes are sometimes noted. Hiccough is an occasional symp- 
tom. The tongue when protruded may be drawn to one side. 
In cases of recent infection the spleen may be only slightly or 
not at all enlarged ; in other cases it may be greatly enlarged, 
constituting a valuable diagnostic sign. 

The liver may be tender, but is usually not much enlarged. 
The evacuations of bowels and bladder may be involuntary or 
there may be retention of urine. The bowels are often con- 
stipated. 

In favorable cases the coma gradually fades, consciousness 
slowly dawns, the temperature drops to or below normal, the 
pulse regains its normal characteristics, and, save the physical 



CLINICAL HISTORY 207 

weakness and a degree of mental hebetude, all is well with 
the patient. 

In unfavorable cases the coma becomes absolute, the pulse 
becomes rapid, thready, and irregular, the breathing is stertor- 
ous and of Cheyne-Stokes type, tracheal rattling appears, the 
face becomes cyanotic, and death ensues from convulsions or 
from collapse. 

The duration of an attack is from a few hours to a few 
days. 

Hertz 183 speaks of cases of "apparent death" arising in the 
course of comatose attacks. He describes these cases as fol- 
lows : 

"Under this form of pernicious intermittent must also be 
classed those cases of apparent death which may last from 
half an hour to four hours. Persons subject to such attacks 
may remain entirely conscious, seeing and hearing everything 
that occurs or is said around them, but unable to move or to 
utter a sound ; or they may be entirely unconscious, respiration 
arrested, pulse and heart beat not to be recognized, and even 
the sharpest irritants applied to the body calling forth no signs 
of life until, at the beginning of the sweating stage, the 
patient comes to himself and the various organs again slowly 
manifest their activity. Trousseau reports the case of a man 
who had had fainting fits on two occasions in Algiers, and in 
a subsequent attack fell into this condition of simulated death. 
It was not until he had been carried into the post-mortem room 
that evidences of life were observed about him, whereupon he 
was returned to his bed and recovered under quinine treat- 
ment." 

Relapses may occur after the apparently favorable deferves- 
cence of the symptoms. Laveran 1 saw three successive attacks 
in a soldier. Colin 86 reports several examples of pernicious 
attacks assailing the same subject repeatedly at intervals of 
fifteen to twenty days. Mayer states that in a third of the 
cases another attack supervened in eight or ten days. More 
than three are very rare, but Homem 1 " records the case of a 
young student who died after having six pernicious paroxysms. 
It has long been maintained that the third attack is fatal. It 



208 THE STUDY OF MALARIA 

usually holds true that the successive paroxysms increase in 
severity and danger to the patient. In the interval the patient 
may be apathetic or may complain of headache. The relapse 
may appear in the form of a different type of pernicious 
paroxysm, as algid or choleraic, but such cases are very rare. 

As intimated, the apoplectic form of pernicious malaria is 
merely a fulminant variety of comatose malaria. In these rare 
cases the onset is equally as sudden as in cerebral hemorrhage, 
whence the name. Laveran, 1 Cardamatis 287 and Crespin 14 * are 
inclined to doubt the existence of this variety, but cases have 
been reported by Morris, 288 Davidson, 66 Maurel, 75 and others. 
Ewing's case is remarkable. "The patient, while sitting up in 
bed smoking, three times in five clays suddenly became uncon- 
scious, his pipe fell to the floor, and he remained stuporous 
for three or four hours. At the end of that period he would 
wake up, at once pick up his pipe, and resume smoking." 

Symptoms originating from the cerebellum are present in 
rare instances. Such are slow, monotonous speech, drowsiness, 
severe depression, and incoordination of voluntary movements. 

Marchiafava and Bignami 22 describe as follows the interest- 
ing bulbar symptoms which occasionally present themselves: 
"When a physician unexpectedly encounters this disease he is 
easily inclined at the first glance to think that the case is one 
of a patient with bulbar paralysis who has become infected 
with malaria, but this suspicion disappears after a careful ex- 
amination and after seeing the gradual resolution of the symp- 
toms. The chief symptoms are : Difficulty in articulation, which 
may even reach anarthria ; a weak and nasal voice ; inferior 
facial paralysis, often of one side only; a half-open mouth from 
which drools the saliva; a pendent lower lip; a dry and only 
slightly movable tongue ; difficult or abolished deglutition. If 
the attack tends to a fatal issue we have the added symptoms 
of sopor, a thready intermittent pulse, labored and stertorous 
breathing, and clammy sweat. When, however, the result is 
favorable the patient recovers from the more severe symptom 
as soon as the fever falls ; the bulbar symptoms usually persist 
for some days, although in milder form, and then gradually 
disappear, the dysphagia going first, then the dysarthria and 



CLINICAL HISTORY 209 

nasal voice, and the paresis of the lower part of the face. Two 
or three weeks may elapse before resolution is complete. If 
the malarial infection has not been properly treated we shall 
have an exacerbation or even a return of the bulbar symptoms 
in the relapses. With these symptoms there are sometimes 
associated disturbances of equilibrium which recall the stagger- 
ing gait of cerebellar disease." 

Cases in which hemiplegia occurs have sometimes been de- 
scribed as the hemiplegic form of pernicious malaria; cases 
with aphasia as the aphasic form. These two are not infre- 
quently associated. Paraplegia is a very rare development in 
pernicious malaria. 

A mild delirium is frequently present in the cerebrospinal 
forms of pernicious malaria. When it is conspicuous it forms 
the so-called delirious type. In this probably more than in 
any other form do predispositions have a causal part, espe- 
cially alcoholism, nervous predisposition, mental fatigue, and 
exposure to solar heat. Delirium in this condition may vary 
from quiet to maniacal. Cases resembling rabies have been 
designated Intermittens hydro phobic a, and are thus described : 
"Violent maniacal delirium, with a frequent pulse, red glowing 
face, and clonic spasms of the muscles of deglutition on drink- 
ing or even at the sight of water; these spasms then pass to 
the muscles of the face, the eyes, and the neck, and finally to 
those of the entire body, a disposition to bite being at the same 
time developed." 183 

Convulsive or eclamptic pernicious malaria is a variety of 
the comatose type in which convulsions are a prominent feature. 
It is especially common in children. The convulsions may be 
confined to certain muscle groups or may be general. In one 
of my cases the little patient had twelve convulsions in an hour. 
Epileptiform convulsions have been described, but it is probable 
that most of these cases are complicated with true epilepsy, as 
the case of Marchiafava and Bignami. 162 

Cases in which the symptoms resemble more or less closely 
those of tetanus constitute the tetanic type of some writers. 
These cases are said to have been relatively frequent in the 
French campaign in Madagascar. 226 Ziemann 48 records a 

14 



2IO THE STUDY OF MALARIA 

typic case. The most prominent symptoms are usually tris- 
mus and opisthotonos; emprosthotonos and pleurosthotonos 
are but rarely observed. 

Occasionally amaurosis arises in the course of a comatose 
attack. It may be transient or, in rare instances, permanent. 
In the only case occurring under my observation vision began 
to improve at the end of the attack, but was not fully restored 
until after several weeks. According to Poncet, 101 the per- 
sistence of amblyopia in these cases is due to optic neuritis, 
peripapillary edema, extravasation of leukocytes, plugging of 
retinal and choroidal vessels by parasites or pigmented leuko- 
cytes, and consequent multiple hemorrhages. 

A rare form of pernicious malaria, the ataxic, has been 
described, particularly by Angellini and Torti. 67 The prin- 
cipal symptoms are scanning speech, dysarthria, weakness of 
lower limbs, vertigo, unsteady gait with a disposition to fall 
forward, muscular tremors, and exaggerated reflexes. Maurel 73 
records 22 cases, but it appears that some of these cases at 
least do not belong to the ataxic type. 

Manson 59 thus describes the so-called ardent fever: "In the 
course of what seemed to be an ordinary malarial attack, the 
body temperature, instead of stopping at 104° or 105° F., 
may continue to rise, and, passing 107° F., rapidly mount to 
no° or even to 112° F. The patient, after a brief stage of 
wild, maniacal, or perhaps muttering delirium, becomes rapidly 
unconscious, then comatose, and dies within a few hours or 
perhaps within an hour after the onset of the pernicious symp- 
toms." Both the cases of. this type observed by Homem 157 
ended fatally. 

Typhoid pernicious has been most carefully studied by Bil- 
let. 151 In these cases the clinic picture is almost identical with 
that presented in typhoid fever. The temperature is periodi- 
cally intermittent or, as is more common, remittent, and usu- 
ally ranges from ioi° to 103° F., but may reach 106° F. 
There are headache, backache, rapid pulse, torpid digestive 
tract, sordes, splenomegaly, apathy, and stupor. There may 
be diarrhea or constipation, and bilious vomiting occurs in 
some cases. The abdomen is usually tympanitic and there 



CLINICAL HISTORY 211 

may exist tenderness and gurgling in the right iliac fossa. 
Epistaxis is frequent. Incoherent speech, delirium, and incon- 
tinence of urine and feces are symptoms of severe cases. All 
of Billet's 40 cases showed the presence of malarial parasites 
and a large mononuclear leukocytosis, and an absence of rose 
spots and the Widal reaction. The average duration was four 
or five days. 

Thoracic Forms. — The immunity of the organs of the chest 
to localizations of the malarial parasites and to the effects of 
their toxins is remarkable. Indeed, the thoracic forms are 
much rarer than the records would import, for the older 
writers especially were prone to attribute any complication that 
might present itself to the effect of the mysterious malarial 
poison. 

Ewing 179 has minutely recorded a case in which the autopsy 
showed an enormous number of parasites in the capillaries of 
the heart muscle. The symptoms referable to the heart were 
feeble pulse, 124 to the minute, and very feeble heart sounds 
on auscultation. The patient was comatose. Benvenuti 179 has 
reported a case in which the capillaries of the myocardium, 
brain, and kidney were filled with infected red cells. , The prin- 
cipal symptoms were coma and dyspnea. 

Formerly cases of pneumonic pernicious malaria were more 
frequently reported than at present. Since more exact methods 
of observation have come into use it is certain that many of 
these cases were complicating lobar pneumonias. That the 
malarial parasite is unable to cause true inflammation of lung 
tissue is now widely recognized, and was maintained by 
Colin, 233 Jaccoud, 289 Roux, 161 and Marchiafava and Bignami. 162 
Nevertheless, grave symptoms referable to the lung, and more 
or less resembling pneumonia, may arise in malarial infections. 
Laveran, 1 who doubts the existence of a pneumonic pernicious, 
admits that in certain patients attacked with intermittent fever 
there may be observed, with each attack, pulmonary conges- 
tion, accompanied with subcrepitant rales, which may lead to 
a belief in the existence of a pneumonic intermittent. Bacelli 
proved the existence of a group of cases nearly resembling 
pneumonia in symptomatology. The characteristic cough, 



212 THE STUDY OF MALARIA 

dyspnea, and pain in the side are present. There may be 
moderate dulness and coarse, sonorous, and sibilant rales 
heard over the portion of the lung involved. Other writers 
describe intermittent lung symptoms and signs met in cases 
of pernicious malaria. Le Dantec 226 records the following 
case, occurring in the person of his friend, Dr. Grosset, who, 
after several paroxysms of intermittent, was taken in the 
course of an attack of fever with dyspnea. Percussion showed 
incomplete dulness throughout the entire extent of the chest. 
Auscultation revealed crepitant rales. The face and finger 
nails were cyanosed, the intelligence was unimpaired, but the 
peripheral sensibility had almost disappeared. The chest was 
covered with cupping-glasses, and several hypodermic injec- 
tions of quinine were given. This alarming condition lasted 
almost twenty-four hours, when, at the moment a fatal issue 
was expected, the sensibility returned and every trace of pul- 
monary congestion disappeared as if by magic. Cases pre- 
senting profuse hemorrhages from the lungs and nose have 
been recorded but rarely. 

The pathogenesis of this condition is not known, as there 
have been insufficient post mortems. From analogy with find- 
ings in other forms of pernicious malaria these cases must be 
attributed to accumulations of parasites in the pulmonary capil- 
laries. Griesinger 290 early compared the filling up of the lung 
that takes place in these cases to the enlargement of the 
spleen. 

Abdominal Forms. — The representative type of abdominal 
pernicious malaria is the algid. The reasons for classing this 
type as an abdominal form have been briefly stated when con- 
sidering the pathogenesis of the different varieties. The pic- 
ture presented is that of abdominal shock, it is peritonism 
minus the peritonitis. 

Torti believed that the algid attack was merely the intensi- 
fication of the cold stage of a malarial paroxysm. But there 
are essential differences. First, the algid attack almost always 
occurs during the febrile period and does not correspond in 
time to the first stage. Secondly, in the cold stage of the ordi- 
nary paroxysm the patient experiences a sensation of chilliness; 



CLINICAL HISTORY 213 

in the algid attack the patient feels that he is "burning up," 
while the skin feels cool to the observer. The algid symptoms 
may appear insidiously, but much more frequently supervene 
after the course of one or more simple paroxysms. Usually 
the first symptoms that attract the attention to the condition 
of the patient are the bad pulse and cold surface. Soon the 
Hippocratic facies is assumed. The eyes are deeply sunken 
and surrounded by dark circles, the nose appears sharp, the 
alse nasi dilate with respiration, the tip of the nose and the 
ears are icy cold. The temples and cheeks are hollowed, the 
cheek bones project, the pupils are dilated, the conjunctivae 
bluish white, the eyes have a peculiar anxious expression, and 
the breath is cool. The skin is pale, having the appearance of 
absolute bloodlessness rather than that of cyanosis. The sur- 
face of the body is bathed with a clammy sweat, is cold, and 
gives the sensation to the hand of handling a catfish. The 
fingers and toes often have the shrunken appearance of the 
washerwoman's hand. The prostration is extreme and the 
voice is weak, low, and cracked. The patient complains of 
burning heat within and begs piteously for cold drinks, which 
are, as a rule, immediately rejected by the stomach. The 
intelligence remains clear and occasionally "the patient, over- 
come by sad apprehensions, considers himself lost, bewails his 
situation, but is not delirious," though usually he is indifferent 
to his peril. The temperature may be subnormal or slightly 
elevated, seldom reaching 104° F. The pulse is rapid, fili- 
form, of low tension, and often intermittent. Later it usu- 
ally becomes imperceptible at the radial. The heart sounds are 
extremely feeble. The respiration is very rapid, superficial, 
and frequently interrupted with deep sighs. The tongue is 
tremulous, cold, and usually moist and smooth. Vomiting is 
a common symptom. The bowels are sometimes constipated, 
but often loose. The abdomen may be slightly tympanitic, or 
scaphoid and tender, especially in the upper half. The urine 
is scanty, highly colored, and of high specific gravity. The 
duration of the attack is short, rarely longer than twelve 
hours after the onset of algidity. In fatal cases the symptoms 
progress rapidly and the patient dies as if in peaceful sleep. 



214 THE STUDY OF MALARIA 

In favorable cases the character of the circulation and respira- 
tion improves, the body warmth is gradually restored, the 
patient ceases to complain, and convalescence is impeded only 
by the extreme weakness. 

When, in addition to the symptoms of algidity already de- 
tailed, there exist symptoms simulating true cholera, there is 
the variety of algid malaria usually spoken of as choleraic 
pernicious. The onset is with profuse diarrhea and vomiting. 
The stools are thin and watery and often rice-water-like. 
There may likewise be shown the muscular cramps of the 
lower limbs frequent in cholera. The temperature is usually 
elevated and pains in the abdomen and precordia and singultus 
may be experienced. The urine is usually scanty and may be- 
come suppressed. 

The condition of algor with which drenching diaphoresis 
occurs constitutes the so-called sudoral or diaphoretic form 
of pernicious fever. These sweats, which are so profuse that 
not only the clothing of the patient, but also the bedclothes are 
saturated, usually supervene toward the close of a paroxysm. 
The celebrated Torti, who was himself the victim of such an 
attack, says that he was just congratulating himself upon 
escaping the fever when the abundant sweats occurred to con- 
vince him that his condition was critical. 

In the course of an algid access syncope occasionally occurs 
when any exertion, even the slightest, is attempted or when 
the patient's head is lifted from the pillow. This dangerous 
symptom usually comes quite unexpectedly, and if the patient 
survives the first onset a subsequent one may rapidly prove 
fatal. 

The gastralgic or cardialgic type is characterized by excru- 
ciating pain in the abdomen, especially the epigastric region, 
or in the precordia. The pain is often so intense that the 
patient doubles up and rolls in agony upon the bed. The 
abdomen is tender and vomiting is a common symptom. There 
may be hematemesis, sometimes profuse. Diarrhea and singul- 
tus are occasional symptoms. 

While the existence of dysenteric pernicious malaria has 
been denied by Colin 291 and more recently by Kanellis and Car- 



CLINICAL HISTORY 215 

damatis, 292 the frequent occurrence of severe dysenteric symp- 
toms, due solely to malarial infection, has been definitely dem- 
onstrated by Craig. 293 The attack may follow other forms of 
abdominal pernicious or may come on suddenly. There are 
frequent actions of bloody mucus, violent tenesmus, colicky 
pains in the abdomen, elevation of temperature, and sometimes 
emaciation. Algid symptoms are not common. Occasionally 
abundant hemorrhages from the bowels occur. They may 
prove rapidly fatal, especially if the patient is already mark- 
edly anemic. 

Icterus and bilious vomiting are not rare in malaraia. As 
a rule, these are not grave symptoms, but there are cases in 
which their persistence and intensity form a complex of symp- 
toms described as bilious pernicious malaria. The fever is 
usually high, nausea constant, icterus marked, and vomiting 
of bile distressing. Bile is present in the urine, often in quan- 
tities, and sometimes albumin. Epistaxis and hematemesis 
have been noted. The epigastrium is often painful and singul- 
tus may add to the discomfort of the patient. Toward the end 
of the severe cases there are apathy and carphology, and the 
scene usually closes with delirium and coma. 

Waton 290 observed a case with symptoms resembling those 
of peritonitis. Laveran 1 refers to several similar cases. Gil- 
lot 294 treated 3 cases in which the clinic picture was identical 
with that of acute peritonitis. One case which he diagnosed as 
perforation due to typhoid ulceration was operated upon. The 
operation proved a mistaken diagnosis. The blood was exam- 
ined, malarial parasites found, and the patient recovered 
promptly after the subcutaneous injection of 1^2 grams of 
quinine. 

Wolf, 295 Chamberlain, 296 and Craig 297 report cases presenting 
symptoms which would lead to a diagnosis of appendicitis. 
Ford 180 records 5 such cases, one of which was operated upon 
and the appendix found to be healthy. 

Ross and Daniels 298 performed an autopsy on a man who 
was not supposed to have died of malaria, and found a hemor- 
rhagic pancreatitis with extensive massing of parasites in the 
pancreas. Parasites were also very numerous in the capil- 



2l6 THE STUDY OF MALARIA 

laries of the stomach and intestines, and these organs showed 
extensive necrosis. 

The urine is usually highly colored. The amount varies 
inversely with the quantity of sweat, bowel movement, and 
vomited matter, the specific gravity varies inversely with the 
amount. Early in the attack albumin may be absent, though 
later it is often present in large quantities, together with 
numerous tube casts. 

The blood in various forms of pernicious malaria shows, 
besides parasitic findings previously mentioned, a pronounced 
reduction of red cells, averaging a half to one million per 
paroxysm. Polychromatophilia of red cells may be observed. 
Contrary to the case of simple malaria, there is usually a pro- 
nounced leukocytosis. There may be as many as 35,000 per 
cm. Thayer 98 observed a case of the algid type in which there 
were 50,000 in number. The differential formula usual in 
malaria, the relative increase of large mononuclear elements, 
is maintained. According to Billet, 151 the average of these 
cells is 10-15 per cent. ; in 9 of his 40 cases it varied from 20-25 
per cent., and in 1 case they existed in the proportion of 30 per 
cent. Great numbers of these cells were pigmented. 

HEMOGLOBINURIC FEVER 

Hemoglobinuric fever is known by many names, some of 
which are mere localisms. Among the more general synonyms 
are: malarial hematuria, hemoglobinuric fever, swamp fever, 
blackwater fever, bilious hematuric fever, melanuric fever, etc. 

After a severe chill the temperature rises rapidly and a 
copious discharge of red, almost black, urine is voided. The 
patient complains of headache and pain in the loins and epigas- 
trium, and is afflicted with nausea and violent bilious vomiting. 
Thirst is torturing and insatiable because of the gastric dis- 
turbance. There may be more or less tympanites. The liver 
and spleen, especially the latter, may be enlarged and tender. 
In a few hours icterus begins and the patient soon becomes as 
yellow as a pumpkin. He is very restless and has an anxious 
expression. If the attack is mild the duration may not be 



CLINICAL HISTORY 



217 



longer than that of an ordinary malarial paroxysm , the vomit- 
ing ceases, pain disappears, the urine gradually clears, the 
temperature falls to normal or a little below, and the patient is 
comparatively comfortable excepting a degree of weakness. 
The jaundice usually lasts a day or two longer. In rare cases 
the duration of the attack is extremely short, the urine voided 
at a single act only being hemoglobinuric. 

In severer cases the temperature may drop, but not to nor- 
mal ; vomiting is incessant, the urine continues darkly colored 
and becomes scantier. Rigors may occur at irregular intervals, 
followed by a rise of temperature, deepening of the color of 



U] 
Ctf 

H 
< 

U 

0. 

H 


m, m. 

300 

290 
280 
270 
260 

250 
240 
230 
220 
210 
200 
190 
180 
170 
160 


DAY OF | 
DISEASE I 






"" 






DAV OF 

MONTH 














HOUR. | '■ 












CENT. 
410— 

40°— 

39°— 

3S°- 

3>- 

36°- 

3S»— 


FAH. 1 

106° 
105° 
104O 
103* 




























• 


































101° 
100* 

990 

•98« 
970 
960 




:f 












1 












/ 


\[ 












y\ 


y 


V* 


..;.. 


: 


















; 






h 














Fig. 59. — Hemoglobinuric fever ; mild. Fig. 60. — Hemoglobinuric fever ; death. 

the urine, and marked prostration. The urine may become 
suppressed and death takes place in a few days. Or the patient 
may die suddenly while being raised to use the vessel or to 
take medicine or nourishment. 

The attack may be preceded by one or more malarial parox- 
ysms or may come on suddenly. There may be prodromata 
consisting of general malaise, aching in the loins and head, 
nausea, and a slight rise of temperature, though this latter may 
be imperceptible to the patient. In more than nine-tenths of 



2l8 THE STUDY OF MALARIA 

the cases the onset is with a rigor, usually intense and pro- 
tracted. Sometimes, as in ordinary malaria, the first stage is 
obscure or wanting, and the attack begins with fever and 
vomiting. Occasionally the passage of black water precedes 
the other symptoms, as in one of my cases, where the patient 
had had a mild rigor the day before, but felt well enough to 
ride out on horseback in search of his cow. While five miles 
from home he was dumbfounded at passing an abundance of 
almost black urine. He immediately set out to consult me, and 
had ridden six miles when he was prevailed upon to return 
home. Death from exhaustion occurred on the fourth day. 
Rarely the onset is characterized by violent pain in the abdo- 
men. The intensity of the onset is no guide to the severity 
of the attack. 

There are four symptoms which are present in nearly all 
cases. These are : fever, hemoglobinuria, icterus, and vomit- 
ing. 

There is nothing characteristic in the temperature. Its usual 
range is from ioi° to 105° F. Hyperpyrexia is unusual, 
though very high temperatures have been recorded. Thus 
Marsden 209 noted a case in which the temperature reached 
1 09° F. Cases in which the temperature is normal or sub- 
normal throughout are not unknown ; for example, 2 reported 
by Baldwin Seal. 258 Neither of these patients had taken any 
quinine. As a rule, in mild cases the temperature reaches the 
fastigium shortly after onset, from which point it drops pro- 
gressively to or a little below normal. In other cases it is 
intermittent, remittent, or irregular, and may resemble the 
curve of septic fever. When rigors occur during the course 
they are accompanied by a rise of temperature. Periodicity is 
not a conspicuous feature nor is the characteristic curve of 
Marchiafava and Bignami seen. The average duration of the 
fever is from a few hours to several days. It usually outlasts 
the hemoglobinuria, but not in all cases. The height of the 
temperature in hemoglobinuric fever is possessed of little or 
no prognostic import. 

A rare occurrence is the obstinate tenacity or subsequent rise 
of the fever after hemoglobinuria has subsided. The duration 




Fig. 6 1. — A convalescent from blackwater fever. The line indicates the border 

of the spleen. 



CLINICAL HISTORY 219 

of this posthemoglobinuric fever is variable. In 2 of Brem's 215 
cases it was fourteen and eighteen clays; in 3 of my cases 
twelve, nineteen, and twenty-eight days; in 1 of Bank's 210 
over five weeks ; in 1 of Howard's 216 six weeks. Outbursts of 
hemoglobinuria occasionally occur during this fever. In most 
of the cases the temperature rose higher than during the hemo- 
globinuric period. It is entirely uninfluenced by quinine and 
is probably related to the spodogenous fever of Marchiafava 
and Bignami, 22 or postmalarial secondary fever. The mortal- 
ity of these cases seems to be low. 

Schellong 92 observed a peculiar case which showed a post- 
mortem elevation of temperature. The fever began to rise a 
few minutes after death, and more than an hour later, when 
last recorded, the temperature was 106.2° F. The ther- 
mometer registered higher in the right axilla than in the left 
throughout the observation. 

Probably in no other condition do we see such rapid and pro- 
found transition in the state of the urine. A few hours before 
the onset the urine is normal, afterward it may show all the 
characteristics detailed below. In favorable cases the return 
to normal is remarkable. 

The quantity varies within very wide limits. In mild attacks 
it may not vary from that of health. Often at first there is 
an increase, a decided decrease at the height of the attack, 
gradually increasing to normal or above with improvement. 
In suppression cases there is usually a diminution from the 
first, resulting in total anuria or the passage of only a few 
ounces daily. Anuria is due to the plugging of the renal 
tubules and to diminution of blood pressure. Pain resembling 
that of renal colic may be experienced with anuria. The tem- 
perature may remain normal throughout suppression of several 
days' duration. It occasionally happens that urinary secretion 
is reestablished after anuria has persisted, even as long as five 
days ; in such cases, however, most die of complications during 
convalescence. The outlook is very grave when suppression 
lasts longer than twenty-four hours. Death usually takes place 
after three or four days, though Plehn 5 reports a fatal case 
where life was prolonged twelve days after the onset of sup- 



220 THE STUDY OF MALARIA 

pression, and Kuclicke 51 observed 2 fatal cases in which anuria 
persisted thirteen days. 

The color, often described as "port wine," varies from a 
light claret to that of black coffee. The latter color obtains 
when the urine of a severe attack is examined in a thick layer 
by reflected light. In a test-tube by transmitted light it ap- 
pears of a lighter color. The froth varies from yellow to red- 
dish ; a greenish color is said to be due to the presence of bile. 
The coloring matter is more often in the form of methema- 
globin, though oxyhemaglobin is found. It is probably not 
present in a true solution, since it is more abundant in the 
sediment of a centrifugalized urine than in the supernatant 
fluid, and disappears from the latter first with improvement. 
The hemoglobinuria may be intermittent or continuous. Ste- 
phens and Christophers 118 observed that blackwater urine made 
alkaline with potash and then boiled produced a purple color, 
giving the bands of hemochromogen, showing that the urine 
itself contained reducing bodies. A. Plehn mentions that on 
boiling the urine and allowing it to stand for some time a 
bright purple color appears. On standing an abundant dirty 
brownish sediment is deposited, the amount varying with the 
concentration of the fluid. The urine stains linen a dirty red. 
The reaction is generally slightly acid, but may be neutral or 
alkaline. The specific gravity varies inversely with the quan- 
tity. Albumin is always present. It is commonly in excess 
of the hemoglobin and persists for a longer period, though the 
curves run more or less parallel. Serum albumin, albumose, 
globulin, and nucleo-albumin are found. Plehn 5 gives the 
limits of quantity as ^2-2 grams per liter, estimated according 
to Esbach's method. The writer has very frequently observed 
twice as much as his maximum limit, and in 1 of his cases the 
amount was 14 grams with the Esbach instrument. Some 
urines on being boiled become almost completely solidified. 
Bile is, as a rule, absent; it is never present in proportion to 
the polycholia. It was not found by the Plehns 5 or by Daniels 57 
in any of their cases. Urobilin is common. Stephens and 
Christophers 118 assert that it occasionally appears before the 
attack, but more constantly after the oxyhemoglobin has dis- 



PLATE XH 



Mo aulzjl- 

' fth^T ^ — **' 

Jemp. 1 •■ : 3 '. : J ' 5 ' J I A > 

— -ft -a j — 

108 -i^-- j-|: 

107 3j 3- : 


Admitted Oij^ju x <f /^^ 

V ' ** II ^ T r-tJt, I-I— T^-I *6*<pQ*k± i.1 2(7 

"" * " ' * I f~ 

J3 * . g, 1 I 

i ^ : i x 




100 _fe-J_* ._» • 

^M — H i 

105 J-J^J -^ 1 

104 -| ~ 

j . . 

103 


: 4 : " = i i4 : X - * =3= -±— 
* < » • — f i 1 — 1 

— ^ a 1- 1 -4- r4 : H ' 

•1 ■ f 

::fr:: = -:A:: = ::-::-::::::±::::::s:-:::::- 


— « 1 

i — --! ===^= 

:: : : :::i- 

: «: 

::::::::::::::::: ir 

*-5 


io?*""*"""—^-^ 1 A j? 


-55 £4 . * *f^ ^~ * * 


f J 1 


-j-3y t- -5 


41 w -j 4 r*3^ A A £R r V £*0 


L r"t ^ J 




IP 1 ^ ■ '^ 1 5 ^V -/ ^ n r 3 g -\ 


, » — f — V , «— 


ivi jj ~ ■ ^ * 


4 ' 4r- *** 3 t- £ 5 3 C J L.-^ i 7 




1-s H £„r ^_ v^ ^ ^-2 3J3 v 


5J v y ^ v ^p 


100 -;-• V - ; 3 *; 


? ■ 13 z Jit 


-.2 "^^^ S k \ 


~I -\ ^ v * 


- 1 1 *j 


— 1 *- — - v \y ; 


99 ^ -3 - 


^ i . j 


j 


■ 




™ 


98 **\- - - 








r -*-t__ .$ i i i: i. _; ; £. 




97 "^ ^ f7-« . t^ t r 


« ' «. I' * '■ ! < _!■ * 


, 


*.~ \*" 1 "a!ft , * ,- fl~i~ s"3~ — - 


u im ^ 




96 ^l -r- x Sfl»*>^-#< — T*-^~ 


r "" "■ _ { r c- i_ _J ; 


-*■-*-* * -1 * 


Temp. „. + ' T » tj. [I T i J i J 


j K « K « & 


< t t * * 5 1 


«n *§.!£• '_! Li. . 


, _ _ 1 . 




•*• «. /LX 






SlOOlS ii < 




* *— ■* — — = — ■* aailae- *- 


Urine z,e ! * ,< " 


l4;/ , j-;^ 4?;^ */^ e jti« *'?» *■"!■« i*f 


'< ?/ 


T" T"T -FT - " 
£1 1 » <M < p 


,r- 7 | V % ,* u '( >*■ 


i r 1 r 1 ~i r n r T 



Posthemoglobinuric fever (after Brem). 



CLINICAL HISTORY 2 21 

appeared, or together with it. Marchoux 299 maintains that 
quinine cannot be detected in the urine during the hemoglobin- 
uric period, but appears later. But the observations of Giemsa 
and Schaumann 300 do not sustain this opinion. They found the 
amount of quinine excreted with the urine during the attack 
is somewhat larger than otherwise, and that the excretion is 
extended over a longer period of time in a regularly increas- 
ing and decreasing curve which is uninfluenced by the hemo- 
globin content of the urine. This increased excretion of 
quinine in the urine in hemoglobinuric fever would lead to the 
inference that the organism is not capable, as it usually is, of 
protecting itself from the poisonous alkaloid by splitting the 
molecule. Marchoux 299 claims that hemoglobinuric fever 
urine has no hemolytic action on the red blood-cells of normal 
persons. 

On microscopic examination the field appears littered with 
a brownish amorphous detritus, the products of broken-down 
red blood corpuscles. Whole red blood-cells are not generally 
found and rarely in considerable numbers. Casts are abun- 
dant, especially the granular; also hyaline and epithelial. 
These casts are sometimes almost covered with the granular 
pigment. Renal and vesical epithelium are common, and 
mucus and crystals of hematoidin may be found. Leucin and 
tyrosin are rare. Williams, 301 Mackey 302 and Brem 215 have 
described different peculiar bodies found in the urine. The 
nature and significance of these bodies are unknown. 

There are often present vesical tenesmus and pain over the 
bladder. Retention of urine, burning in the urethra, and ten- 
derness over the kidneys are not uncommon symptoms. The 
urine may be voided drop by drop. 

After a few hours jaundice begins to appear and, except in 
the mildest cases, develops rapidly until the skin and sclera 
are of a pronounced saffron yellow. It usually outlasts the 
fever a few days. Itching of the skin is not common. Herpes 
is relatively infrequent and petechias are rare. The occurrence 
of the latter is said to imply a grave prognosis. Edema or 
anasarca may be encountered, especially in cases where there 
is unusual involvement of the kidneys. Sweats may occur with 



222 THE STUDY OF MALARIA 

the decline of the fever or with collapse. The skin is often 
dry. Sometimes the perspiration is charged with bile pigment. 
Banks 210 mentions a peculiar odor emanating from blackwater 
fever patients. He claims that it enables one, together with 
the expression, to make a diagnosis before the urine is exam- 
ined. So far as the writer knows, he has not been corrobo- 
rated, though in suppression cases a uremic odor may be per- 
ceptible. 

Vomiting is usually one of the earliest symptoms and fre- 
quently the most distressing. After the stomach contents are 
voided the vomit consists of a yellowish or green bile. Occa- 
sionally it is a grass-green or peculiar bluish-green, or it may 
be very dark, almost black, somewhat resembling the black 
vomit of yellow fever. The vomiting is independent of the 
taking of food, and is probably more or less of central origin. 
In very mild cases vomiting may be very insignificant or 
absent. Nausea is usually in proportion to the vomiting. The 
bowels may be constipated or there may be a bilious diarrhea. 
Occasionally the dejections are thin and watery, of a reddish- 
brown color, and may closely resemble the urine. 

This is thought to be due to the extravasation of hemoglo- 
binuric serum into the intestine, and is usually seen in severe 
cases only. Dysenteric symptoms are infrequent. Hemor- 
rhage from stomach or bowel is rare. Meteorism is not an 
infrequent symptom. There may be severe colicy pains in the 
abdomen. Pain is usually present in the epigastric region or 
over the liver and spleen. These are usually tender, the spleen 
often greatly enlarged, the liver less so. The appetite in all 
but mild cases is completely lost. Thirst is intense and cannot 
be alleviated for the vomiting. The tongue is anemic and 
heavily coated. Sordes of the teeth and lips are often seen in 
extreme cases. The saliva may stain the linen a brownish- 
yellow. The pulse is rapid, out of proportion to the tempera- 
ture, at first full and bounding, later small and compressible. 
A hemic murmur, systolic in time, is sometimes heard over the 
precordia, not transmitted. Respiration is accelerated. There 
is often sense of oppression in the chest. Dyspnea may be a 
prominent symptom, due to anemia or to edema of the lungs. 



CLINICAL HISTORY 223 

There may be, especially after some days of severe illness, 
slight dulness and diminished respiratory murmur over the 
dependent portions of the lung, accompanied by slight cough, 
resulting from hypostatic congestion. Cheyne- Stokes respira- 
tion may appear toward the end. Hiccough is present in a 
large per cent, of fatal cases, and if obstinate is always to be 
regarded unfavorably. Epistaxis is occasionally seen. 

Anemia increases with intense rapidity, half the red cells 
sometimes being destroyed in twenty-four hours. The number 
usually falls to one to two million during the attack. Except 
for the absolute diminution of the fluid portion of the blood 
as a consequence of purging and vomiting, the number of red 
cells per c.mm. would appear much smaller than it does. It 
is occasionally difficult to obtain a drop for examination by 
the usual method. It appears relatively thinner than normal 
and the cover-glass may adhere to the oil-immersion objective 
rather than to the slide. On coagulation the serum may appear 
yellow (cholemia) or reddish (hemoglobinemia), though 
neither is constant. Macrocytes, microcytes, poikilocytes, 
shadows, polychromatophiles, and basophiles are found, but not 
always, as pathologic cells may succumb early. One is often 
surprised to see, notwithstanding- the extreme hemolysis, the 
erythrocytes presenting so few changes. Nucleated reds may 
be found, especially during' convalescence. The color index 
shows nothing characteristic; it may be normal or above, at 
first falling gradually until convalescence is established. The 
hemoglobin per cent, usually runs parallel with the red cell 
count. It is generally reduced to 25 to 50 per cent., sometimes 
lower, as in a case of Hoffmann, 49 in which the patient recov- 
ered notwithstanding a fall to 12 per cent. It is often asserted 
that during pyrexia there is a leukocytosis, and the polymor- 
phonuclears are increased often to 90 per cent. With falling 
temperature there is a pronounced large mononuclear increase 
with leukopenia. However, the average of a number of differ- 
ential counts made at irregular intervals during the attack 
shows a marked increase in the large mononuclears, a decided 
diminution of small mononuclears, and a slight increase of 
polymorphonuclears. Pigmented leukocytes are common. 



224 THE STUDY OF MALARIA 

Christophers and Bentley 303 have made interesting observations 
on the phagocytosis of red blood corpuscles in the spleen of a 
case of blackwater fever. In a differential count of 2,200 
spleen cells 1.7 per cent, were large macrophages containing 
red cells and 1.3 per cent, were small mononuclear cells con- 
taining red blood-cells. In both kinds of cells were seen blood 
corpuscles showing no evident alterations, corpuscles more or 
less decolorized, and clear vacuoles about the size of red blood- 
cells. The closest scrutiny of the engulfed cells failed to reveal 
the presence of parasites or other evidence of parasitic invasion. 
This extensive phagocytosis of apparently normal cells is of 
interest from the standpoint of pathogenesis. The platelets 
are numerous and of large size. The alkalinity of the blood is 
often diminished. In spite of the destruction of red cells the 
specific gravity remains relatively high. This is no doubt due 
to the quantity of material in solution in the serum. During 
convalescence the specific gravity falls. Stephens and Christo- 
phers 57 give the following as the result of their observation on 
tonicity : "In blackwater there is occasionally a remarkably low 
tonicity; in other cases it has the normal value or somewhat 
raised value, as in malaria. The low or normal value in black- 
water may be due, as we have previously suggested, to the fact 
that the weak corpuscles — those of high tonicity — are de- 
stroyed, or it may be due to the fact that the tonicity of the 
corpuscles as a whole is changed after the liberation of hemo- 
globin." The presence of malarial parasites has been dealt 
with. 

Blackwater fever is not a very painful affection, but the 
vomiting and thirst make the patient intensely wretched. Be- 
sides the abdominal pains there are headache and aching of the 
back and limbs. He is usually terrified at the appearance of 
the urine. His expression is one of anxiety and apprehension, 
and a fear of death often seizes him. He is restless and irri- 
table. In children especially there is frequent tossing of the 
head from side to side. Later there is prostration, intense 
languor, perhaps somnolence. Formication and numbness in 
the fingers and toes are occasional complaints. Delirium when 
present is usually quiet. When suppression ensues the symp- 



CLINICAL HISTORY 225 

toms may be typic of those in uremia, but this is not con- 
stant; delirium may be of the low, muttering variety; convul- 
sions are often missing, and the mind may be clear until 
shortly before death, when coma supervenes. There may be 
involuntary discharge of urine and feces. 

The causes of death are three : Suppression of urine, exhaus- 
tion, and cardiac paralysis. Suppression is the commonest 
cause. This sometimes takes place when the urine is clearing 
or is already clear. Uremic symptoms do not result from sup- 
pression in blackwater fever as frequently as in other condi- 
tions. This is probably due to two causes. First, elimination 
through vomiting and purging is free ; secondly, metabolism is 
diminished as the result of deficient oxygenation. Exhaustion 
is usually the result of the tremendous destruction of blood- 
cells, together with inability of the hematopoietic organs to 
meet the deficiency, or to pyrexia. Occasionally hiccough plays 
a role in exhaustion. The patient may die early with symptoms 
of shock or may linger several days in a typhoid state. Cardiac 
paralysis is usually due to thrombosis of the heart. Plehn 5 
regards this as a common cause of death. Goltmann and 
Krauss 189 have shown that in some cases of death from syncope 
there exists a marked cardiac nerve degeneration and empty 
c)dinders. 

It would manifestly be of great practical importance if the 
symptoms of an impending attack of hemoglobinuria could 
be recognized. This is possible, if at all, only in a very 
general way. Plehn 24 says that an onset is to be feared 
when the patient has lived some six months in a blackwater 
fever area and has had malaria at short intervals, when this 
malaria has been treated improperly with insufficient quinine 
dosage, when he looks downcast, and perhaps shows a mild 
icterus of the sclera and skin. This might, however, forebode 
a relapse of ordinary malaria. Sometimes, he further states, 
there occurs a certain depressed condition, a characteristic 
mental apathy with physical restlessness, phenomena which are 
hard to describe, but have often been encountered by one who 
has seen many cases develop. Also the presence of albuminuria 
should cause suspicion, as this tends to be absent in simple 

15 



226 THE STUDY OF MALARIA 

tropic fever, even with a temperature of 41° C. Koch 90 des- 
ignates as "blackwater fever candidates" those in whom a 
few hours after taking quinine the temperature mounts to 
38° C. or more, the urine becomes decidedly darker, and the 
next morning a mild icterus is evident. Ziemann 48 has fre- 
quently observed in blackwater fever candidates the following 
blood changes, which, however, are not constant: 

1. The more frequent appearance of decided basophile and 
polychromatophile degeneration of the red cells. 

2. The rapid solution of the red cells in a salt solution, in 
which normal cells do not dissolve. 

3. A decided diminution of the coagulability of the blood. 
This writer also regards urobilinuria as a valuable prognostic 

sign. 

Relapses are not infrequent and several may occur, often 
befalling the patient when he is thought to be doing well. It 
may be difficult to distinguish relapses from recurrences. 
Convalescence may very properly be regarded as the dividing 
line, those occurring during convalescence being considered as 
relapses and those later as recurrences. Plehn 208 believes that 
recurrences are rare unless provoked by quinine. Of eighteen 
recurrences recorded by Vedy 213 one occurred after less than 
three months, fourteen from three to six months, two from six 
to twelve months, and one longer. It is remarkable that nine 
recurrences happened just three months from the date of the 
last attack. The writer's experience has been that in persons 
having more than one attack the attacks are more often sepa- 
rated by intervals of a year or more. 

Complications and Sequela?. — These are singularly few in 
variety. Nephritis in some degree is an almost constant com- 
plication, and may cause death from suppression during the 
attack. It may heal in a remarkably short time. As a sequela 
it is not infrequent and may persist for days or weeks, causing 
slow and incomplete convalescence or death. The changes in 
the kidney may be attributed to the irritating effect of hemo- 
globinuric urine and to the pyrexia. 

In 16 cases the writer has been able to make examinations 
of urine at periods varying from a few days to fourteen years 



CLINICAL HISTORY 227 

after the last attack. In 8 cases the examination was negative. 
The others may be noted as follows : 

F. S., white, male, set. 17, one attack, 1899; urinalysis, Feb- 
ruary 27, 1907, showed a trace of albumin, no casts, no symp- 
toms of nephritis. 

A. J., white, male, set. 18, two attacks, last one October, 
1904; urinalysis, September 21, 1906, showed albumin % g m - 
liter, very numerous cylindroids and hyaline casts, moderate 
number of granular. Anemia, edema of lids and ankles. 

Mrs. H., white, female, set. 25, one attack fourteen years 
ago; urinalysis, September 25, 1906, showed the presence of 
albumin and a few granular casts. No symptoms. 

M. C, white, female, set. 10, two attacks, last one Septem- 
ber 24, 1906; urinalysis, on October 8, 1906, showed a moder- 
ate amount of albumin, no casts. Anemia, edema of face and 
ankles, indigestion. 

E. C, white, female, aet. 7, five attacks, last one November 
15, 1906; urinalysis, December 4, 1906, nitric acid test for 
albumin negative, microscope showed a very few cylindroids 
and hyaline and granular casts. 

R. A., mulatto, male, aet. 44, one attack November 13, 1905 ; 
urinalysis, August 22, 1906, showed no albumin, moderate 
number of cylindroids, and a few hyaline casts. 

J. P., white, male, set. 37, several attacks, last one September 
21, 1907; urinalysis, July 28, 1908, a slight trace of albumin, a 
few hyaline casts, very few granular. 

W. S., white, male, aet. 42, one attack, which occurred Feb- 
ruary, 1905; urinalysis, June 27, 1908, no albumin, a few 
cylindroids. 

The possibilities of the abnormalities of urine and the symp- 
toms in the cases being produced by other causes than the 
hemoglobinuria should be borne in mind. 

Anemia and consequent debility and digestive disturbances 
are not uncommon. Rare complications are : paraplegia, tetanic 
convulsions, purpura hemorrhagica, dysentery, pneumonia, 
pancreatitis, abscess of the liver, erysipelas, parotiditis, retinal 
hemorrhage, pleurisy, and neuralgia. The writer has seen 
tonsillitis once as a complication. 



228 THE STUDY OF MALARIA 

CHRONIC MALARIA 

There is a great deal of confusion as to what is compre- 
hended by chronic malaria. Much of this chaos is due to 
including the manifestations of malarial cachexia with those 
of chronic malaria, between which, however, there are essen- 
tial differences. Chronic malaria implies a supply of vital 
resistance equal to the demand; malarial cachexia denotes an 
exhaustion of this supply. Chronic malaria is an antagonistic 
equilibrium between parasite and host; cachexia, a rupture of 
equilibrium. Chronic malaria is a conflict, cachexia a con- 
quest. The relation between chronic malaria and cachexia has 
been fitly compared to that existing between a compensated 
heart lesion and broken compensation. Chronic malaria is an 
active form of malaria, cachexia is a sequel. Cachexia being 
a sequel, usually of chronic malaria, it may be difficult to say 
where the influence of the latter ends and the former begins. 
On the other hand, it is frequently difficult or impossible to 
differentiate between a relapse in chronic malaria and a re- 
infection. 

For convenience of study, chronic malaria may be divided 
into a latent or passive stage and an active stage, or stage of 
relapse. 

It is more frequently observed in children. It has already 
been shown that the frequency with which children native to 
the soil are infected constitutes the true endemic index of a 
locality. 

Chronic malaria may be due to one infection, but occurring 
chiefly in regions where repeated reinfection is possible, it is 
highly probable that reinfection is an important factor. 

An analysis by the writer of a large number of cases shows 
the following results : Quartan and tertian infections are more 
prone to relapse than eslivo-autumnal. The percentage of 
relapses to total number of cases of quartan, tertian, and estivo- 
autumnal is, respectively, 65, 55, and 45. The pertinacity of 
quartan may be regarded as a conservative effort of nature to 
perpetuate the species. It is, indeed, remarkable how this form 
of the parasite is conserved in certain places where it is so very 
rare. However, the greater tendency to relapse shown by the 



CLINICAL HISTORY 229 

benign infections is more than counterbalanced by the severity 
of the symptoms of the estivo-autumnal relapses. Hence it is 
undoubtedly true that the estivo-autumnal parasites are the 
most important factors in chronic malaria. 

It is the parthenogenetic cycle of the parasite that is chiefly 
concerned in the pathogenesis of chronic malaria, though the 
asexual forms also have a role. The parthenogametes are the 
parasites of the latent stage, the schizonts of the active stage. 
Parthenogenesis is the bridge across the gap caused by inter- 
ruption of the schizogonic cycle. 

The most frequent course is for chronic malaria to follow 
one or more acute attacks. In some instances, however, the 
latent stage may precede the active. Thus it is not extremely 
rare to meet cases with evidences of chronic malaria which 
have no history of active manifestations. 

The latent stage of chronic malaria resembles in some re- 
spects a period of incubation ; in fact, the cases reported 
with unduly long stages of incubation are doubtless nothing 
but latent stages of the chronic disease. During the latent 
stage parasites may or may not be found in the peripheral 
blood. 

Symptoms during the latent stage may be altogether absent, 
in which case latency is absolute, or there may be present cer- 
tain symptoms, subjectively insignificant, constituting relative 
latency. These symptoms are ordinarily similar to the pro- 
dromata of acute malaria : malaise, loss of appetite, aching of 
the back and legs, digestive disorders, etc., together with 
anemia and enlarged spleen. Latent malaria is the source of 
very numerous infections, and is of the utmost importance 
from the viewpoint of prophylaxis. 

The duration of latency is exceedingly variable. Relapses 
occur at shorter or at longer intervals. 

Relapses at short intervals have been recognized since the 
time of Hippocrates. Later the septenary periods were noted 
for a tendency to show relapses, and this idea is still largely 
prevalent among the laity. This shorter interval of latency 
corresponds more or less closely to the sexual cycle of the 
parasite and to the period of incubation. It is also in harmony 



230 THE STUDY OF MALARIA 

with the law of Treille 304 and with the studies of Cohen 305 
upon the period of freedom from paroxysms following a single 
injection of quinine. The duration of this period is from five 
to twenty-one days, oftenest from five to ten. Relapses at 
shorter intervals occasionally exhibit a striking periodicity. 

Relapses at longer intervals occur at from one to twelve 
months, exceptionally longer. Very long periods of freedom 
have been recorded, even up to sixty years. 306 Undoubtedly 
many of these are errors, due either to mistaken diagnosis or 
to the occurrence in the interval of unrecognized or masked 
paroxysms. However, periods as long as three years have 
been reliably recorded. 48 

It being clinically impossible to distinguish between a relapse 
and a reinfection, the writer has adopted Celli's 80 rule, it being 
equally adapted to the seasonal prevalence of malaria in this 
country. This authority regards as a relapse every case of 
fever which repeats itself in the same individual during the 
epidemic year of malaria, from July of one year to the end 
of the following June. It is true that this may include some 
cases of reinfection, but it is unquestionably the most practical 
guide and eliminates a maximum of error. 

Secondary etiologic influences play a much more prominent 
role in relapses than in primary infections. Of these the most 
important are change of residence, fatigue, abuse of alcohol, 
exposure, and gastro-intestinal disturbances. All are familiar 
with the frequence with which a change of residence "brings 
the malaria out." These influences are much commoner factors 
in the relapses at long intervals than in those at shorter inter- 
vals. 

It is ordinarily the relapse that brings the chronic malarial 
to the physician. The relapse may consist of one or more 
typic malarial paroxysms or they may be atypic. Very often 
the first stage of the paroxysm is wanting. They may exhibit 
quotidian, tertian, or quartan periodicity, or may be altogether 
irregular. The patient usually has an anemic tint and may, in 
advanced cases, be jaundiced. Occasionally the complexion 
may be earthy, at other times bronzed. The skin is dry and 
often scaly. The eyes may be deep set; they often bear a hag- 



CLINICAL HISTORY 231 

gard, restless expression. The patient appears aged beyond his 
years. The condition of nourishment is poor, and there may 
be edema of the face and feet. There are weakness of arms 
and legs and an indisposition to physical exertion. The pulse 
is accelerated, weak, and sometimes irregular. Percussion 
may reveal an increase in the cardiac dulness, and auscultation 
an anemic murmur. Dyspnea on slight exertion, a feeling of 
weight or pain in the precordia, and palpitation are not infre- 
quent symptoms. 

The extent of the blood destruction depends upon the sever- 
ity and proximity of the paroxysms and the activity of the 
blood-making organs. The number of red cells frequently 
falls to one million per c.mm. or even less. In other cases the 
destroyed cells are nearly replaced within a short time after 
the relapse. The hemoglobin percentage is sometimes dispro- 
portionately lower than the red cell count, though occasionally 
it may be normal or above. The leukocyte formula is similar 
to that of acute infections. Parasites of the asexual cycle are 
usually found in the peripheral blood. Tertian gametes are 
frequently seen, while quartan are rare. The frequency of 
crescents and ovoids is very variable. In my experience they 
are very rarely seen in blood obtained from the superficial 
circulation. They are also infrequent in the experience of 
Manson 59 (in cases seen in the tropics), A. Plehn, 171 Craig, 307 
Stephens and Christophers, 11S Ziemann, 308 Wellman, 309 Annett, 
Dutton and Elliott, 310 Kendall, 30 and others. The majority of 
observers, however, have seen estivo-autumnal gametes in a 
considerable proportion of their cases. In localities where this 
phase of the parasite is so rare it is rather difficult to under- 
stand how the species is preserved. The most probable ex- 
planation is that the sexual cycle is supplanted by the partheno- 
genetic cycle in the perpetuation of the species, the partheno- 
gametes tending to congregate in the spleen. 

Other blood changes, as nucleated red cells, microcytes, 
macrocytes, and poikilocytes, are more common in chronic than 
in acute malaria. 

The respiration is usually quickened, especially after exer- 
cise. Chronic bronchial catarrh, usually of a mild degree, is 



232 THE STUDY OF MALARIA 

not a rare condition in chronic malaria, and epistaxis is some- 
times profuse. 

Digestive disorders are very common and marked meteorism 
may exist. The condition of the bowels is not constant, diar- 
rhea sometimes alternating with constipation. Dysenteric 
manifestations are frequent. 

The spleen may be of normal proportions in mild cases, but 
is usually enlarged, sometimes enormously so, passing the 
median line of the abdomen and the iliac crest. It may or may 
not be tender or painful ; in the former case the pain is usually 
of a pulling nature and referred to the left shoulder. If peri- 
splenitis with adhesions does not occur the spleen may be 
movable or floating. Often the spleen enlarges during the 
active stage to recede slowly during latency. The liver is often 
slightly enlarged and tender. 

Headache, nervousness, restlessness, vertigo, insomnia, and, 
in severe cases, impaired memory, are observed. The urine is 
often albuminous. 

Masked Malaria. — Masked or larvate malaria, like perni- 
cious malaria, needs complete overhauling. Nearly every dis- 
ease in the category has been confounded with malaria and 
classed as larvate. This heterogeneous group has been ex- 
panded to embrace diseases unrelated in any way to malaria, 
diseases complicating malaria, and symptoms and sequelae of 
malaria. The frequency of masked malaria varies inversely 
with the care employed in diagnosis. Masked malaria is merely 
atypic malaria. The symptoms being of little value in diagno- 
sis, this must be made by the anamnesis, the microscopic ex- 
amination of the blood, and by the therapeutic test. Nervous, 
gastro-intestinal, and cutaneous disorders are those most fre- 
quently recorded as masked. Most of these are to be consid- 
ered under Complications and Sequelae. 

COMPLICATIONS AND SEQUELS 

Circulatory System. — Malaria is very frequently complicated 

by heart disorders. In the negro population of the South, in 

whom syphilis, abuse of alcohol and tobacco, pneumonia, and 

other etiologic factors are very prevalent, lesions of the cir- 



CLINICAL HISTORY 233 

dilatory system, particularly valvular lesions of the heart, often 
add to the gravity of severe malarial infections. These are to 
be regarded almost invariably as complications and not as 
sequelae. Circulatory lesions, the direct result of malarial in- 
vasion, are remarkably rare. Many such cases were reported 
before the discovery of the parasite, but are for this reason 
practically valueless. 

Collin 227 found cardiac hypertrophy in 6 of 61, and Kelsch 
and Kiener 178 in 34 of 80 autopsies on malarial subjects. It is, 
however, by no means certain that malaria was responsible for 
the hypertrophy in these cases. 

Probably the commonest cardiac sequel of malaria is myo- 
carditis. Slight evidences of degeneration of the heart muscle 
are sometimes found after death in cases which presented no 
symptoms during life. Triantaphyllides 311 observed 26 cases 
with symptoms of myocarditis in 12,000 cases of malaria; these 
cases he believes due solely to malaria. The cases of so-called 
asthenia cordis following malaria are probably cases of myo- 
carditis. Dilatation may follow myocarditis. Localizations of 
parasites in the blood-vessels of the heart have been mentioned 
when considering pernicious malaria. 

Angina pectoris is occasionally observed in connection with 
malaria. It may exist as a complication or as the cardialgic 
type of pernicious malaria. 

Much was formerly written about malarial endocarditis, 
aortitis, and endarteritis. These occur but rarely and only as 
complications. Ulcerative endocarditis has occasionally been 
observed after pneumonia complicating malaria. It should be 
borne in mind that the temperature of septic endocarditis may 
be similar to that of malaria. Pericarditis and aortic aneurism 
are unusual complications. Phlebitis and thrombosis have been 
seen, more often in cases of cachexia. 

There is absolutely no evidence that malaria is a causative 
factor in either lymphangitis or lymphadenitis, the so-called 
malarial bubo, these conditions occurring only as complica- 
tions. A suppurating bubo, like other septic processes, may 
be accompanied by an intermittent temperature. 

Respiratory System. — Coryza may occur as a complication 



234 TH E STUDY OF MALARIA 

to malaria, especially during unseasonable weather. Bronchitis 
is a common complication, during - a portion of the malarial 
season occurring with marked frequency. It is observed 
oftener in the negro than in the white race. Subacute or 
chronic bronchitis is usually in chronic malaria and cachexia. 

Ziemann reports the case of a healthy young man who, dur- 
ing an attack of estivo-autumnal malaria, was afflicted with 
intermittent spasm of the laryngeal muscles. The spasms 
coincided with the malarial paroxysms, parasites were found 
in the blood, and both the malaria and the laryngeal trouble 
yielded promptly to quinine. 

A peculiar condition of the pulmonary apices has been de- 
scribed. It consists of a rapid and a transient congestion of 
the apex of one or both lungs, arising and disappearing with 
the paroxysm. The cough is dry and painful, the expectoration 
is scanty, occasionally bloody, and there may be bronchial 
breathing and increased vocal fremitus. The writer has had 
no experience with this complication. 

Pneumonia was long considered a manifestation or a sequel 
of malaria, but it is now known that they are entirely distinct 
diseases. 

Either lobular or lobar pneumonia may complicate malaria, 
the latter more frequently than the former. Lobar pneumonia 
sometimes occurs with acute malaria, but much more com- 
monly with chronic malaria and cachexia. It is probably the 
most frequent mode of exit of the cachectic, in whom the 
pneumonia often assumes the low form and is especially liable 
to complications, as delayed resolution, gangrene, abscess, and 
pyothorax. Pneumonia complicating malaria is apt to be 
atypic, though the pneumonic symptoms usually predominate. 
Both lungs are more apt to be affected, profuse hemoptosis 
occasionally occurs, and malarial parasites may be found in 
the expectorated blood. Fibroid pneumonia sometimes com- 
plicates malarial cachexia. The prognosis in malaria compli- 
cated with pneumonia is grave. 

Pleurisy is not a common complication of paludism. It has 
been maintained 312 that the enlarged spleen, especially if peri- 
splenitis exists, predisposes to inflammation of the left pleura, 



CLINICAL HISTORY 235 

but this requires further evidence. Hydrothorax may rarely 
be present in cachexia. Jenness 313 has recently recorded a fatal 
case of abscess of the right diaphragmatic pleura during an 
attack of tertian malaria. The chief physical signs were flat- 
ness on percussion, and absence of respiratory and voice 
sounds; there was no bulging of the chest wall. At autopsy 
the liver was found normal. 

Gastro-intestinal Tract. — Stomatitis is sometimes observed 
in malaria. Parotitis is an infrequent complication. Dyspeptic 
symptoms denoting chronic gastric catarrh are not uncom- 
mon in cases of chronic malaria and cachexia. Gastric ulcer 
in association with amyloid changes in the mucosa is rarely 
noted. Hematemesis occasionally assumes alarming propor- 
tions. 

Enteritis is a much more frequent sequela of malaria than 
ordinarily regarded. The inflammation may advance to ulcera- 
tion. The process has been frequently demonstrated by autop- 
sies to be due to accumulations of parasites in the intestinal 
mucosa. Diarrhea is common, especially in persons improperly 
fed. Profuse hemorrhage occasionally occurs, in which case 
the microscopic examination of the blood is of the greatest 
value in differentiating the disease from typhoid fever. 

Dysenteric symptoms arising in the course of malaria and 
the dysenteric form of pernicious malaria have been consid- 
ered. Well-marked dysentery may be present either as a com- 
plication or as a sequela. Often the dysenteric symptoms pre- 
dominate, thus constituting one of the commonest forms of 
masked malaria. Craig 164 has shown that 65 per cent, of the 
patients with malarial parasites in the blood observed at the 
Army General Hospital, Presidio of San Francisco, suffered 
at some time from acute or chronic dysentery, and of these 
more than 25 per cent, suffered from amebic dysentery. 
Thayer 98 says that nearly 12 per cent, of the cases of amebic 
dysentery treated at the Johns Hopkins Hospital have suffered 
simultaneously with malaria. In 36 cases of dysentery asso- 
ciated with malaria Ewing 27 found the Amoeba dysenterica in 
the stools of 9. Dysentery aggravates the prognosis of malaria. 

Besides the ameba, other intestinal parasites may complicate 



236 THE STUDY OF MALARIA 

paludism. Of these by far the most common is the Ascaris 
lumbricoides. Uncinariasis is not an infrequent complication 
in some sections. The writer has observed an infection with 
Hymenolepis nana associated with malaria. It is not improba- 
ble that intestinal helminthiasis aggravates the anemia and 
the gastro-intestinal and nervous symptoms. In examining 
the blood for the malarial parasite the presence of eosinophilia 
calls for an examination of the feces. 

Cirrhosis of the liver, the direct result of malarial infection, 
described as relatively frequent in certain portions of the 
tropics, appears to be rare in this section. Hypertrophic 
hepatitis may result from prolonged infection. Ascites occa- 
sionally develops, particularly in chronic malaria and cachexia. 

The Blood and Spleen. — Leukemia follows malaria only 
rarely, probably never as a true sequela. In 124 cases of leuke- 
mia Mosler 79 determined that only 8 or 10 bore any etiologic 
relation to malaria. Marchiafava and Bignami 22 observed a 
case of splenomedullary leukemia in an adult male, aged 
twenty-eight. The symptoms were enormous enlargement of 
the spleen and liver, diarrhea, and grave anemia. The case 
had been diagnosed malarial cachexia. Bastianelli 67 observed a 
similar case. Ziemann 48 treated a case in the ten-year-old 
daughter of a Duala chief; the girl had suffered repeated at- 
tacks of malaria, and pigmented leukocytes were found in the 
blood. Sakorraphos 79 described 10 cases of leukemia in per- 
sons who had formerly lived in malarial localities. However, 
the blood examination showed no parasites nor was there any 
elevation of the temperature. Brown 79 saw a case of lymphatic 
leukemia follow malaria. The writer has had no experience 
favoring an etiologic relation between leukemia and malaria. 

The relation of splenic anemia (Banti's disease) to malaria 
is not clear. Two of Hemmeter's 314 cases followed malaria, 
and of 15 which Osier 316 observed malaria preceded 5. Cohen 
and Rosenberger 315 observed a case of chronic malarial infec- 
tion with spleen and blood lesions closely resembling those of 
Banti's disease. Injections of quinine and urea were used with 
good results. Splenic anemia may come into consideration in 
differential diagnosis. 



CLINICAL HISTORY 237 

Malarial Cachexia. — In this condition the parasites have 
obtained undisputed possession of the host. The defensive 
forces have been completely conquered, the blood-making or- 
gans can no longer meet the demands made upon them, and 
toxins, unopposed, work changes, often irreparable, in impor- 
tant organs. Cachexia has been classified as dry or humid, 
according to the absence or presence of anasarca, and as acute 
or chronic. Acute cachexia is characterized by a rapid onset 
and development of symptoms, and usually follows acute mala- 
ria, occasionally after only one or two attacks. These cases 
are infrequent. Chronic cachexia, the usual form, is a sequela 
of chronic malaria. 

Malarial cachexia is found where the severe forms of mala- 
ria are endemic. It may be stated as a general rule that the 
frequency of cachexia among the white race is an index to the 
prevalence of grave infections. It is much more common in 
the white race than in the negro. While negro children are 
not infrequently the subjects of malarial cachexia, it is much 
rarer in the adult negro. Of adults, males are more commonly 
cachectic than females ; among children the proportion is about 
even. The condition rarely develops in persons of the better 
class, but is seen in those living under improper hygienic con- 
ditions and who neglect the treatment of acute malaria. 

Cases of cachexia developing without preceding malaria have 
been reported, but are subject to question. The malaria may 
have been unrecognized, as might happen with latent or masked 
infections. In regions where kala-azar is endemic it is only 
recently that this disease has been differentiated from malarial 
cachexia. Infections with the estivo-autumnal parasites are 
followed by cachexia much more frequently than tertian and 
quartan infections. 

The cachectic usually presents a singular appearance. The 
emaciated limbs are in marked contrast to the big belly, and 
the features are aged beyond the years. The most pronounced 
phenomena are the anemia and the enlarged spleen. The red 
blood-cells may be reduced to seven or eight hundred thousand 
per c.mm. The leukocytes are generally normal in number 
or a little below. Numerous differential counts have shown a 



238 THE STUDY OF MALARIA 

relative increase of the large mononuclear elements. The red 
cells may show basophile degeneration, polychromatophilia, 
poikilocytosis, and nuclei, but none of these changes are by 
any means constant. According to my experience parasites 
are rarely found in the peripheral blood. The spleen often 
extends to the umbilicus and to the crest of the ilium, some- 
times beyond. It is usually hard and the anterior border pre- 
sents a sharp edge. Pain and tenderness on pressure are not 
always felt. Occasionally a bruit is to be detected over the 
splenic area. 

The pulse is small, compressible, and may be irregular. Pal- 
pitation of the heart and hemorrhages, especially epistaxis, 
may occur. An anemic murmur over the precordia is often 
heard. Myocarditis and dilatation are not infrequent. The 
breath is short, sometimes amounting to actual dyspnea. A 
cough is common and signs of bronchitis may be elicited. Pul- 
monary edema is a late symptom. 

The temperature may be normal or subnormal for long 
periods, though evening rises are often observed. Typic parox- 
ysms are not frequent. Fever often follows imprudences. 
Whether the fever of cachexia is due directly to parasitic activ- 
ity or to organic changes is not definitely known. The appetite 
is generally poor and the digestion tardy. Epigastric pain, 
nausea, and vomiting may be complained of. The tongue and 
oral mucous membrane are pale. Diarrhea and dysentery fre- 
quently occur. Meteorism is common. The liver is usually 
somewhat enlarged at first; later it may become atrophic. 
Ascites is not a rare manifestation. When fever exists the 
urine is ordinarily scanty and highly colored. Delayed de- 
velopment of the genitals is common in the young and dimin- 
ished sexual power is not rare in the adult. Indifference, intel- 
lectual torpor, somnolence, headache, and vertigo are observed 
in cachectics. Resistance to cold is lessened and rheumatic 
pains are experienced. The skin is pallid, dry, and rough, and 
may exhibit sores or purpuric spots. Anasarca may supervene. 

Pneumonia, dysentery, hemoglobinuric fever, and nephritis 
are common complications of cachexia, and amyloid degenera- 
tion, especially of the kidneys, an occasional sequela. Peri- 




E 



fe 



bD 
E 





a, 




>> 




H 


*+ 


1 


MO 


1 




M3 


hn 


VO 






k4 


IN 




VO 




CO 




W) 








Hh 



bC 
E 



CLINICAL HISTORY 239 

splenitis occasionally occurs and may be the cause of severe 
pain, especially if adhesions take place. A heavy spleen may 
cause relaxation of its supports and become "floating" or "wan- 
dering." This condition is seen more often in multiparous 
females. By pressure on neighboring organs a wandering 
spleen may cause pain, digestive disorders, or even intestinal 
occlusion. The pedicle may become twisted, as occurred in a 
fatal case of Marchiafava and Bignami. 22 

Rupture of the spleen is an infrequent complication of mala- 
rial cachexia. It is very rarely associated with acute malaria, 
though a case has been recorded by Palmer 317 in which rupture 
occurred within seven days of the onset of the fever. The 
writer observed a case in a subject of cachexia who had a 
large, hard spleen. Recovery followed, notwithstanding ex- 
tensive hemorrhage. In some countries, especially in India, 
rupture of the spleen has assumed medicolegal importance. 
According to Brault, 318 it is popularly known in Kharkov that 
the malarial spleen is very friable, and that combatants engaged 
in fist fights strive to strike the region of the spleen, with the 
result that 5 per cent, of the official autopsies show ruptures 
of this organ. The rupture may be spontaneous or the result 
,of blows and falls. Of 19 cases of rupture of the malarial 
spleen collected by Messerer 319 15 were spontaneous and only 
4 the result of trauma. However, 35 cases studied by Russell 95 
were due to trauma, and no cases of spontaneous rupture were 
noted. A large, soft spleen is much more liable to rupture than 
a hard one, and fatal hemorrhage is more apt to occur in the 
former case. A full stomach predisposes to splenic rupture, 
especially of the concave side. The capsule is usually ruptured, 
but when thickened, as may result from previous perisplenitis, 
it may escape untorn. The capsule was not ruptured in only 
1 of Russell's 95 35 cases. The laceration occurs with about 
equal frequency on the concave and convex sides of the spleen. 
Tears of the inner aspect may occur without marks of violence 
of either the skin or the convex surface of the spleen. A light, 
sharp blow tends to injure the convex surface ; a fall or crush- 
ing blow, the concave side. The symptoms of rupture of the 
spleen consist of violent pain in the splenic region referred to 



240 THE STUDY OF MALARIA 

the left shoulder, together with evidences of shock and hemor- 
rhage. The mortality of cases not treated with splenectomy 
is exceedingly high. Death may occur in from a few hours 
to five days. 

Abscess of the spleen is a rarer complication of malaria even 
than rupture. The writer is able to collect from the literature 
mention of not more than 50 cases. The common pyogenic 
cocci and the bacillus coli communis are the bacteria usually 
present in splenic abscesses. The symptoms are sometimes as 
vague as those of abscess of the liver. There may be pain in 
the left hypochondrium, especially if the abscess is superficial 
and the peritoneum is involved. The pain is often referred to 
the left shoulder. Pain may, however, be entirely wanting. 
The temperature is usually elevated, though in rare instances 
may be normal or subnormal. It is usually intermittent and 
associated with chills and sweats. Emaciation may be extreme, 
notwithstanding the appetite is sometimes voracious. Abscess 
of the spleen may be confused with uncomplicated malaria, and 
renal, gastric, or pancreatic disease. The presence of leuko- 
cytosis and the therapeutic test are valuable diagnostic points. 
Signorelli's spleen point may be a useful guide. This is a 
painful area corresponding to the fifth intercostal space near 
the left nipple. The examination of the urine may mislead. 
In a case of splenic abscess observed by Goltman 320 the urine 
contained albumin, casts, pus cells, renal cells, and some red 
blood-cells. Aspiration is attended with some danger, bat may 
be done as a last resort, especially if the patient is prepared for 
operation. The abscess may rupture externally into the pleural 
cavity or lung of the left side, or into the stomach, intestine, or 
peritoneal cavity. Without operation the prognosis is very 
grave; with timely incision and drainage a considerable per 
cent, recover. 

Infarcts and gangrene of the spleen are noted among the 
rare complications of the spleen in malarial cachexia. 

Genito-urinary Organs. Nephritis. — The frequency of ne- 
phritis recorded as a sequela of malaria varies greatly with 
locality, type of fever, and with the idea of what constitutes 
nephritis. Thus, while Ford 180 observed acute nephritis in 



CLINICAL HISTORY 24.I 

only 1.5 per cent, of his cases of malaria, Moore 321 reports the 
percentage as 80. The real frequency of nephritis in malaria 
is in about y 2 to 2 per cent, of the cases of tertian and 
quartan infections and 2 to 5 per cent, in estivo-autumnal. The 
negro is apparently more susceptible to the renal lesions of 
malaria than is the white. More cases are seen in the months 
during- which the estivo-autumnal fevers prevail. The middle- 
aged and the old are less often attacked than the young. 
Nephritis is much more prone to result from chronic than 
from acute malaria. The nephritis is most often acute, but 
it is highly probable that malaria is an important factor in the 
etiology of chronic nephritis. Chronic nephritis may follow 
the acute form or may exist as such from the beginning. True 
hemorhagic nephritis is rare. There is ordinarily nothing char- 
acteristic either in the symptoms or pathologic histology of the 
nephritis of malaria. Ewing, 177 however, has observed an in- 
teresting and unique case of malarial nephritis with extensive 
massing of the parasites in the kidneys. Parenchymatous ne- 
phritis is the commonest type, though the contracted kidney 
may occur as a late lesion. Kelsch and Kiener 178 divide mala- 
rial nephritis into the diffuse or glomerular and the granular 
nephritis of Bright, each with acute and chronic forms. Amy- 
loid degeneration is a renal sequela of malaria. 

Occasionally intense lumbar pain, closely simulating renal 
colic, is experienced as a complication of malaria. This colic 
usually responds promptly to quinine, though the pathogenesis 
is not clear. 

Forms of orchitis and epididymitis have for a long time been 
attributed to malaria. Either may complicate malaria. The 
writer has seen several cases of epididymitis associated with 
malaria, there being, however, in each case a history of venereal 
disease. There is at the present time absolutely no evidence 
that either orchitis or epididymitis is ever a true sequela of 
malarial disease. The same may be said of hydrocele, which 
some observers have ascribed to malaria. 

It is doubtful whether genuine atrophy of the testicles ever 
occurs as the result of malaria. It is more probable that these 
cases are due to improper development, the result of cachexia, 

16 



242 THE STUDY OF MALARIA 

climate, or other factors. Duprey 322 has recently described 
three cases of impotence following estivo-autumnal fever. 
Metrorrhagia and, more often, menorrhagia and amenorrhea 
are not infrequently seen with malaria. Sterility has been 
charged to paludism. 

It was formerly believed that pregnancy conferred a degree 
of immunity against malaria. This is now known not to be 
true. If the pregnant woman is attacked less often with 
malaria it is because she is less often exposed to infection and 
not on account of any immunity which pregnancy confers upon 
her. 

A list of cases is appended to give an idea of the frequency 
with which abortion and premature labor occur as the result 
of malaria complicating pregnancy. The first column of fig- 
ures records the number of cases in which the complication 
appeared; the second column shows the number of abortions 
and premature labors which occurred : 

Pascali 105 34 25 

Weatherly, 159 in India 88 28 

Weatherly, 169 in England 58 2 

Weatherly, 159 in Africa 97 22 

Weatherly, 159 in Florida 52 22 

Hospital, Rome 80 51 33 

Lwow 323 26 10 

Goth 324 46 19 

Bonfils 325 105 73 

Williams 326 _I5 

572 234 

24.4 per cent. 

This percentage is at least twice as large as that resulting 
from my experience. 

The writer is inclined to the belief that the negro is much 
less liable to suffer abortion or premature delivery than is the 
white. This is in keeping with the well-known relative im- 
munity of the negro to some of the effects of malaria. Mer- 
cier 182 has observed an unusually large number of abortions in 
Creole women infected with malaria. It is well known that 
this race is markedly susceptible to the severer forms of 
malaria. 

Cases accompanied by continued high temperature, retching, 
and vomiting, and which are more resistent to treatment, are 



CLINICAL HISTORY 243 

those in which abortion most frequently occurs. Hence it 
follows that abortion is more often due to estivo-autumnal 
fever than to tertian and quartan, and to multiple infections 
than to single. 

The danger of abortion and premature delivery is greater 
in proportion as the pregnancy is advanced. Thus of Goth's 324 
19 cases expulsion of the uterine contents occurred: once in 
the fourth month, once in the fifth month, three times in the 
sixth month, five times in the seventh month, and nine times 
in the eighth month. 

The factors in the interruption of pregnancy are probably 
fever, retching, vomiting, anemia, and toxins. It is not im- 
improbable that in some cases parasitic localizations in the 
uterine vessels excite pains or cause placental separation, 
though for this theory there is as yet no pathologic proof. 

If the malarial infection does not terminate the pregnancy 
the labor at full term is apt to be slow, especially the first stage. 

Children born at full term of malarial mothers are apt to be 
smaller and lighter than normal, and the mortality is higher. 

Labor often rekindles latent malaria, which, in the puer- 
perium, is not infrequently atypic, the first or third stages of 
the paroxysm or complete intermission of the temperature 
sometimes lacking. Subinvolution, postpartum hemorrhage, 
and suppression of milk may occur with puerperal malaria. 

Nervous System. — It is often impossible to determine 
whether nervous manifestations in malaria are complications 
or sequelae. It is certain that many cases reported as due to 
malaria are purely complications. This is the case with mul- 
tiple neuritis, of which numerous cases have been ascribed to 
malaria. In by far the majority of cases the existence of 
malaria was not established by blood examination; in others 
it is not certain that the neuritis was due to malaria. 

Glogner, 327 in the East Indies, described 6 cases of polyneu- 
ritis occurring during and after malarial disease. In 4 cases 
the parasites were found in the blood. The chief symptoms 
were diffuse pains in the lower limbs, formication, tenderness 
of the nerves and muscles, and motor weakness, while the deep 
reflexes were sometimes intact, sometimes abolished. The elec- 



244 THE STUDY OF MALARIA 

trie excitability of the nerves and muscles was diminished, 
while sensibility was retained. Edema of the legs was present 
in some of the cases. 

Price 328 records a case in a girl, eight years old, who fol- 
lowing malarial infection, had multiple neuritis which lasted 
eighteen months. Her symptoms were pain, paresthesia, hand 
tremor, weakness of the extremities, with characteristic foot 
drop. Estivo-autumnal parasites were detected on blood ex- 
amination, and quinine effected a cure. 

Ziemann 48 observed a case of peripheral neuritis in a young 
German merchant who had been in Cameroon four months. 
Two days before his entrance into the hospital he was taken 
with high fever without a preceding cold stage. Simultane- 
ously he noted almost complete paralysis of both legs, espe- 
cially of the right. Neither the bladder nor bowel functions 
were affected, nor was there marked sensory disturbance. 
The temperature did not exceed 103.5° F. The peripheral 
blood showed an enormous number of estivo-autumnal para- 
sites. While the paralysis of the left leg persisted only a few 
days during convalescence, that of the right leg was slow in 
diminishing - , notwithstanding massage and electric treatment 
for several weeks, so that at the end of four months the patient 
was still compelled to walk with the aid of a stick. 

It is not infrequently difficult to differentiate between poly- 
neuritis and myelitis. 

Laveran 1 describes a case of paraplegia which he observed in 
Constantine. The patient had had several attacks of malaria 
and underwent a relapse after admission to the hospital, during 
which the parasite was found on microscopic examination. 
The paralysis of the lower limbs was not accompanied by any 
alteration of sensibility nor of nutrition, and micturition and 
defecation were normal. Unfortunately for an exact diagnosis 
the patient had had syphilis also. Mercury and potassium 
iodide were prescribed without appreciable result. Quinine 
caused a disappearance of the parasites, but had no effect on 
the paralysis. 

A fatal case showing paraplegia was treated by Ziemann 
The patient was a strong negro man. Bladder paralysis, re 



48 



CLINICAL HISTORY 245 

tention of urine, and coma were present. The blood contained 
estivo-autumnal parasites. 

Da Costa's 329 case of paraplegia harbored the estivo-autumnal 
parasite and yielded to quinine. 

Either persistent or intention tremors may. be associated 
with paludism. The case of Da Costa just mentioned exhibited 
intention tremor. Fornaca 330 reports a case in a peasant, aged 
fifty-seven, whose personal and family history were good and 
who, during an attack of malaria, was affected with tremors 
of both arms and hands. These tremors were irregular and 
increased on voluntary motion, but did not cease during rest. 
They became exaggerated during the paroxysm and diminished 
in the interim. Simple tertian parasites were present in the 
blood and the symptoms disappeared upon the administration 
of quinine. 

Torti 331 saw 2 cases in which there were symptoms of multi- 
ple sclerosis without a history of syphilis or the abuse of alcohol 
or tobacco. In both cases parasites were found, and both were 
cured with quinine. 

Spiller 332 has reported a case closely resembling multiple 
sclerosis. The patient, a male, aged forty, gave a history of 
having had a chancre twenty years before. He came under 
observation three years before death, which resulted from 
acute diarrhea, lasting one week and probably of malarial 
origin. The symptoms were a very decided intention tremor 
of the left upper limb; marked ataxia of the left lower limb; 
alternating hemiparesis, first of one side of the body, then of 
the other ; headache, drowsiness, vertigo, and diplopia ; marked 
vertical nystagmus; scanning speech; exaggerated tendon re- 
flexes and ankle clonus on the right side. Post mortem the 
spleen was found to weigh 550 grams. The crossed pyramidal 
tract was moderately sclerotic throughout the cord; this 
sclerosis could be traced as high as the left internal capsule. 
All the capillaries of the brain and cord were filled with estivo- 
autumnal parasites, and numerous small and recent hemor- 
rhages were seen in the left paracentral lobule and other por- 
tions of the cortex. The capillaries observed under a low- 
power lens appeared to have been injected with black powder. 



246 THE STUDY OF MALARIA 

The sclerotic lesions are said not to have resembled those due 
to syphilis, and the symptoms are believed to have been due 
to the parasitic thromboses of the capillaries and not to the 
sclerosis. 

Hemiplegia, paraplegia, and various monoplegias, either with 
or without aphasia or sensory disturbances, are not infre- 
quently associated with malaria. 

Cerebellar syndromes are rarely observed in malaria. They 
consist of general weakness, rigidity, and pain in the back of 
the neck, intense headache, ataxic gait with a tendency to fall 
backward and to the left, tremors, incoordination of move- 
ment, dysarthria, nystagmus, and vomiting. The tertian para- 
site is usually present in these cases. 

Bulbar symptoms are occasionally encountered. Such are 
hypoglossal and facial paralysis, ataxia of arm, dysarthria or 
anarthria, and staggering gait. These symptoms are usually 
obstinate. 

Various psychoses occur in connection with malaria, either 
during or following acute or chronic malaria. The commonest 
of these disorders are weakened memory, melancholia, mania, 
and delusional insanity. Suicidal and erotic tendencies may 
be observed. Below are brief notes on 4 cases under the care 
of Ziemann 333 in Cameroon : 

1. A merchant, thirty-six years of age, slender, pale, with 
a history of neurasthenia but not of alcoholism, living in a very 
unhealthy locality, but using no prophylactic quinine, having 
had several moderate and light attacks of estivo-autumnal 
fever, was suddenly seized with a violent paroxysm. During 
the seizure he had strong delusions of persecution. He seized 
his gun in order to shoot down the neighbors whom he thought 
pursuing him. Energetic quinine therapy was followed by 
complete cure excepting that the idea that the neighbors had 
persecuted him during the night of his illness persisted. 

2. A strong young merchant, with no hereditary taint nor 
alcoholic history, not having employed quinine prophylactically, 
had an attack of estivo-autumnal malaria. During the access 
he distinctly heard the voices of his father and other relatives 
in Europe, and conversed with them upon his prospects in 



CLINICAL HISTORY 247 

Cameroon. Complete cure followed the administration of 
quinine except the fixed idea that his relatives had visited him 
during his illness and that he was more' quiet, peculiar, and 
neurasthenic. He was returned home on the failure of his 
firm. 

3. A young merchant had been in Cameroon two years en- 
gaged in expeditions for the purpose of obtaining rubber. 
During these expeditions he did not use quinine as a prophy- 
lactic, although he suffered repeated malarial attacks. On a 
visit to another merchant he was suddenly taken with a parox- 
ysm during which he distinctly saw an arm extended from the 
wall, holding a revolver aimed at him. Seized with terror, he 
fled to keep from being murdered. Quinine cured the fever, 
but the delusion of the arm and the revolver as to that par- 
ticular time persisted. 

4. A strong young merchant of healthy family and without 
history of alcoholism or nervous disorder was seized three 
weeks after arrival in Cameroon with a severe estivo-autumnal 
infection. During the attack he labored under the delusion 
that his colleagues, who in reality nursed him attentively, had 
planned to kill him. After energetic treatment with quinine 
a complete cure was effected excepting the persistence of the 
fixed idea of persecution by his colleagues. 

Hysteria is not a rare phenomenon during paludism. It is 
probably the result of anemia in predisposed persons. As it 
may assume either of a multitude of forms, its chief signifi- 
cance is from the viewpoint of diagnosis. 

A mild neurasthenia is probably due directly to malaria in 
some instances, and preexisting neurasthenia is often aggra- 
vated by malarial infection. The usual symptoms are restless- 
ness, nervousness, insomnia, and annoying distinctness of the 
heart beat on retiring. 

It was formerly believed that intercurrent malaria exercised 
a beneficial influence upon epilepsy. So far from this being 
the case, however, epilepsy is frequently aggravated by paludal 
infection. 

Violent choreic symptoms are among the rare nervous phe- 
nomena. 



248 THE STUDY OF MALARIA 

The Eye. — Injection of the conjunctiva is not infrequently- 
associated with neuralgia of the fifth nerve. True inter- 
mittent conjunctivitis occurs but rarely if at all. Both inter- 
stitial and dendritic keratitis are occasionally observed with 
malaria, though it is doubtful whether either form can be 
attributed to malaria. The same probably holds true for 
vesicular keratitis or the so-called corneal herpes. In per- 
nicious seizures with coma-vigil the eyes are more or less ex- 
posed to damage. 

Iritis exists as a complication of malaria in rare instances. 
Choroiditis occasionally occurs in connection with retinitis. 
Optic neuritis is observed chiefly in cachectics. In the majority 
of cases it proceeds to atrophy. 

Retinal hemorrhages are oftenest minute and located far 
forward, hence they may be easily overlooked. Occasionally, 
however, they are peripapillary or macular and of large size. 
In the latter case the prognosis is more serious. Persistent or 
periodic amaurosis without evident retinal changes is sometimes 
seen. The writer has seen one case of hemianopia following- 
pernicious malaria of the comatose form which terminated in 
complete restoration of vision. Rarer optic manifestations 
occurring in conjunction with malaria are hemorrhage and 
infiltration into the vitreous humor. 

The Ear. — Otalgia, labyrinthine vertigo, otitis media, and 
lesions of the internal ear and auditory nerve have been de- 
scribed as occurring with malaria, but in no case has the blood 
been examined. 

The senses of taste and smell are said to be diminished or 
abolished in rare cases of malaria. 

The Skin. — The frequency with which herpes occurs in 
malaria has already been mentioned. Next to herpes, urticaria 
is the most frequent cutaneous lesion associated with malaria. 
It may occasionally resemble the eruption of measles. The pos- 
sibility of the eruption being caused by quinine should be re- 
membered. Erythema is not an uncommon eruption with 
malaria, and may simulate the eruption of scarlatina. Pruritus 
may be present. Erythema nodosum has occasionally been 
observed. Petechias and large purpuric spots are not rare in 



CLINICAL HISTORY 249 

subjects of chronic malaria and of cachexia. In these patients 
ulcers and furunculosis may exist as complications. 

The occurrence of herpes zoster in malaria is very variable. 
In 616 cases of malaria studied by Thayer and Hewetson 29 
herpes zoster occurred only once, and this complication existed 
but once in 1,780 cases of malaria reviewed by Anders. 283 
On the other hand, Winfield 33 * found malarial parasites in 
the blood of 14 out of 25 cases of herpes zoster. The writer 
has recently observed 9 cases of herpes zoster. In 3 the blood 
examination revealed estivo-autumnal parasites ; in 2 there was 
a history of recent malaria, but the examination of the blood 
was negative, while in 4 there was no history of recent malaria 
and the examination of the blood was negative. 

As previously mentioned, purpura simplex is not an uncom- 
mon occurrence in malaria. Purpuric eruptions may also, but 
rarely, be noted in hemoglobinuric fever. But true purpura 
hemorrhagica is very rarely seen in malaria. Eisenmann, 
Wenmarning, and Tchouprina, 96 Bastianelli and Bignami, 335 
Hirtz and Bernheim, 86 Marchiafava and Bignami, 102 and the 
writer 336 have reported such cases. 

Malaria undoubtedly predisposes to the development of gan- 
grene, especially when it has become chronic or has advanced 
to cachexia. More than this, however, cannot be said of the 
part played by malaria in the etiology of gangrene. Gangrene 
of almost every part of the surface of the body has been ob- 
served in malarial subjects. The gangrene is more commonly 
of the dry variety. Local asphyxia not followed by gangrene 
occurs also. Raynaud's disease, or symmetric gangrene, has 
been thought to be due to malaria in many instances, but re- 
ports of cases in which the malarial parasite was present in 
the blood are still rare. 

Other Conditions and Diseases. — At various times malaria 
has been supposed to predispose to certain diseases. Such were 
typhoid fever and diabetes. It has also been thought to exert 
an antagonistic influence toward other diseases, as tuberculosis, 
cancer, and influenza. It is probable that any predisposing 
power on the part of malaria to other diseases is only indirect. 
It is a priori improbable that a disease conferring only relative 



250 THE STUDY OF MALARIA 

immunity toward itself should immunize against or antagonize 
other diseases, and such is the result of experience. 

Typhoid Fever. — The complication of typhoid fever with 
malaria is not very rare. A search of the literature reveals 
records of 215 cases in which the presence of malarial parasites 
and the typhoid bacilli or the Widal reaction conclusively 
proved the association. 

Typhoid fever is more frequently complicated with tertian 
than with estivo-autumnal malaria. Craig 337 has reported the 
only case of simultaneous typhoid fever and quartan malaria 
of which the writer has any knowledge. 

Usually the malarial symptoms arise and the parasites are 
detected during convalescence from the typhoid fever, though 
they may be present during the course of the latter. When 
the onset of the malaria precedes that of the typhoid fever the 
malarial parasites often disappear from the peripheral circu- 
lation upon the advent of the typhoid fever, sometimes re- 
appearing and producing symptoms during the convalescence 
from typhoid. This is analagous to the. result of inoculating 
a given variety of malarial parasites into a malarial patient 
harboring a different form, the older infection usually sur- 
rendering to the fresh. Malaria occurring at the height of 
typhoid fever may or may not modify the course of the 
latter. The mortality of the complication of these two fevers 
is higher than that of uncomplicated typhoid. 

The term "typhomalarial fever," if used at all, should be 
restricted to those cases in which exact methods of diagnosis 
prove it applicable. However, the combination of typhoid and 
malarial fevers is no more entitled, either by virtue of intimacy 
or frequency, to a hyphenated appellation than is tuberculosis 
or gonorrhea in association with malaria. It was formerly 
believed that a mysterious fusion of both diseases produced a 
hybrid pathologic entity. It is now definitely known that this 
is not the case. Such a diagnosis is ordinarily a compromise 
based on a lack of frankness to acknowledge inability to diag- 
nose certain cases of fever in the earliest stages, and is not only 
loose and unscientific, but is, in many instances, actually harm- 
ful, as it often leads to the abuse of purgatives and quinine. 



CLINICAL HISTORY 25 1 

There is no question but that nearly all of the so-called "typho- 
malaria" is pure typhoid fever. 

Diabetes. — In spite of the great frequency with which Bur- 
del 86 claims to have found glycosuria complicating malaria (92 
times in 382 cases of malaria), it must be considered a rare 
complication. Ziemann, 48 Wittrock, 49 and Marchiafava and 
Bignami 22 observed 1 case each, and Hemmeter 314 mentions 
records of 198 urinalyses in cases of malaria gathered from 
various hospitals, only 2 of which indicated diabetes mellitus. 
The writer recalls the case of a diabetic, passing more than 5 
per cent, of sugar, who was attacked with estivo-autumnal 
malaria. The latter ran an uneventful course and seemed to 
have no effect on the sugar excretion. The patient died sev- 
eral months later of bronchitis. 

Polyuria in malarial subjects has already been mentioned. 

Tuberculosis. — In the South, where tuberculosis is very 
prevalent in the negro race, the negro death rate from tuber- 
culosis ranging from 100 to 150 per cent, higher than in the 
white race, tuberculosis and malaria not infrequently concur, 
especially in the colored race. Malarial cachexia predisposes 
to tuberculosis only in a slight measure, if at all. The negro, 
who is less often the subject of cachexia than the white, more 
often shows the combination of malaria and tuberculosis. The 
malaria may prove rapidly fatal, both diseases may be un- 
modified in their progress, or the tuberculosis may assume a 
more rapid course. The old idea that the two diseases are 
antagonistic is disproved not only by their not uncommon 
occurrence in the same individual, but Kelsch and Kiener 178 
have even found, in several autopsies, evidence of both dis- 
eases in the same organs, as the liver and spleen. 

Influenza. — Anders 337 believes that there exists a decided 
antagonism between malaria and influenza. Simms and War- 
wick, 85 however, mention simultaneous epidemics of malaria 
and influenza in Alabama, when, "of those infected with mala- 
ria, 60 per cent, were brought down with this disease, and it 
was much more severe than in those who were not infected.'" 

Cancer. — Based on the supposition that cancer is not so fre- 
quent in tropic latitudes, and on the report of Krzowitz, in 



252 THE STUDY OF MALARIA 

1776, of a case of cancer of the breast healing after an attack 
of double tertian malaria, Loffler 338 assumed an antagonism be- 
tween the two diseases, and proposed, as a therapeutic measure, 
the inoculation with malaria of cancerous patients. A few 
experiments and numerous reports of cancer among tropic 
people and malarial subjects have shown the absolute useless- 
ness of such a procedure. On the other hand, it is believed 
that malaria of long standing predisposes to cancer of the liver. 

Smallpox is an infrequent complication of malaria. La- 
veran 1 observed several such cases in Constantine. The mala- 
rial parasites usually disappeared from the blood with the 
onset of the smallpox where the onset of the latter succeeded 
that of the former. The mortality of these cases was unusu- 
ally high. Pyemic foci and hemorrhages were observed. 

Syphilis is a common complication of paludism. Under 
these circumstances syphilis is more rapid in its course and is 
rebellious to treatment in proportion to the chronicity of the 
malarial infection. In malarial cachectics antisyphilitic treat- 
ment is sometimes all but impotent. Syphilitic buboes are 
more apt to suppurate and become ugly indolent ulcers. Mala- 
rial invasion may arouse latent syphilis. 

Vincent 159 is of the opinion that the colon bacillus often as- 
sumes pathogenic importance in malarial infections, and he 
terms the result "coli-malarial fever." The patients are pro- 
foundly malarial ; they present a fever of continued type and 
typhoid phenomena, subdelirium, coma, diarrhea, etc. At 
autopsy there are no intestinal lesions save a few psorenteric 
plagues. Some show extensive foci of necrosis in the spleen 
or small miliary abscesses; others suppurating points in the 
kidneys. Siderosis is found in the spleen and liver. Bacterio- 
logic examination shows a generalized infection with the bacil- 
lus coli commumis. The eccentric and iconoclastic Legrain 25! 
believes that the role of the colon bacillus in exotic pathology is 
immense. 

In the present state of our knowledge it is impossible to de- 
termine the part played by the colon bacillus in the fevers of 
warm countries. In subtropic and tropic climates, with an 
exuberant flora, it is theoretically not impossible that the colon 



CLINICAL HISTORY 253 

bacillus may acquire an unusual degree of virulence and give 
rise to auto-intoxications. Every Southern physician is familiar 
with ephemeral fevers, usually attributed to "biliousness," 
which disappear after the administration of an antiseptic purge, 
as calomel. 

The association of scorbutus and malaria was formerly 
frequently encountered in military practice during campaigns. 
It is now rarely seen, especially in civil practice. 

Valenti 339 and Lioubenetzy 340 have each observed in malarial 
subjects symptoms recalling Addison's disease. 

Malaria in Children. — In older children there is nothing 
unusual in the malarial attacks. In infants and young children 
there are several points which deserve a brief consideration. 

The type of fever is most often quotidian, sometimes tertian 
or double quotidian, rarely quartan. The paroxysm occurs 
more often during the night than is the case with the adult, 
the fever being often detected for the first time in the morn- 
ing. 

The first stage is rarely typic, the rigor being replaced by 
coldness of the extremities, pallor, slight cyanosis, especially 
of the lips and nails; vomiting, drowsiness, and sometimes 
convulsions. During the second stage the fever is ordinarily 
higher than in the adult. Gastro-intestinal symptoms, particu- 
larly vomiting and diarrhea, are common. Thirst is usually 
intense. The most common complaints are pain in the head 
and epigastric region. Enlargement of the spleen is more 
constant than in the adult. Torticollis and erythema may 
be noted. Atypic forms and dangerous symptoms, especially 
on the part of the nervous and gastro-intestinal systems, are 
frequent. Edema, ascites, and purpura are not uncommon. 

Malaria in the Negro. — The relative immunity of the negro 
race to the severe manifestations of malaria and to hemoglo- 
binuric fever has been mentioned. It remains only to cite a 
few clinic features of malaria in this race. 

Estivo-autumnal malaria is much more common in the col- 
ored race than are tertian and quartan. The paroxysms usu- 
ally occur during the day, but night paroxysms are more com- 
mon than in the white race. A well-defined and severe cold 



254 THE STUDY OF MALARIA 

stage, while not at all rare in the negro, is more frequently 
lacking than in the accesses in the white. Herpes is relatively- 
rarer in the black. Uncontrollable vomiting is not nearly so 
frequent in the colored race as in the white. Marked splenic 
enlargement is much less common in the negro, palpable spleens 
in the adult negro being infrequent. The extremely low hemo- 
globin percentages, which are not rare in chronic malaria and 
cachexia of white persons, are far less frequently observed in 
the negro. As previously stated, cachexia is decidedly more 
prevalent in the white race. Malarial parasites are altogether 
absent from the peripheral blood of negroes in a larger per 
cent, of cases than they are wanting in white patients. When 
present they are more frequently scanty. On the other hand, 
the negro may harbor large numbers of parasites without 
manifesting any symptoms. Pulmonary complications, bron- 
chitis, pneumonia, and tuberculosis are more frequent in the 
negro. Nephritis is another complication of which this is 
true. Hysteria and other neuroses are probably more common 
in the colored female. The abuse of snuff, which is under- 
mining the nervous stability of the majority of adult negro 
females in the South, may help to account for this. There 
is less tendency to abort during pregnancy complicated with 
malaria in the colored female than in the white. Spontaneous 
cure after only one or two paroxysms is a common termina- 
tion of malaria in the negro. Every physician practising 
among this race is familiar with the frequency with which 
their attacks of malaria end after a "round" of purgative and 
a potion of "tea" of some sort. The grave forms of malaria 
occurring less often, the mortality is consequently lower in 
the negro race. 

The Surgical Aspect of Malaria. — Trauma may aggravate 
active malaria or arouse it from latency. On the other hand, 
malarial infection reacts upon wounds. Slight wounds, such 
as that caused by the extraction of a tooth, may in cachectics 
give rise to excessive hemorrhage. Fractures heal more slowly 
in malarial subjects. The writer has more than once observed 
suppuration, ulceration, and sloughing in the wounds, aseptic- 
ally treated, of malarial persons, especially sawmill employes 



CLINICAL HISTORY 255 

and timbermen. If surgical measures are contemplated in 
patients with a history of recent malaria the blood should 
be examined carefully for evidences of malaria, which, if 
present, might figure in the result. 

With reference to the surgical relations of malaria the fol- 
lowing conclusions are justifiable : 

1. In subjects of active malaria, wounds are apt to aggravate 
the malaria. 

2. In subjects of latent malaria, trauma is apt to excite the 
latter into activity. 

3. Chronic malaria and cachexia may complicate wounds 
by increasing the tendency to hemorrhage, suppuration, 
sloughing, indolence, or even gangrene. 

4. The mere presence of parasites in the blood without pro- 
ducing symptoms (absolute latency) is no bar to operation, as 
the specific treatment may be pursued with the surgical. 

5. In badly debilitated subjects of chronic malaria and of 
cachexia only operations of necessity should be undertaken, 
and then quinine and tonics should form part of the after- 
treatment. 



CHAPTER VI 



DIAGNOSIS 



Malaria is the scapegoat of tropic pathology and quinine 
the high priest. 

Too often is the mocking equation of Legrain, 

Fever=Malaria=Quinine, 

employed to solve the diagnostic problems of the fevers of 
warm climates. 

There are three sources from which information may be 
drawn to make a diagnosis of malaria; first, from the symp- 
toms; second, from the examination of the blood; and third, 
from the effect of quinine upon the symptoms. 

i. Of the clinical history the most important feature to be 
considered is periodicity. Tertian and quartan periodicity are 
pathognomonic of malaria. Sometimes the statements of 
patients cannot be relied on with respect to the course of their 
ailments, and tertian and quartan periodicity must be abso- 
lutely determined to be of diagnostic value. By this is not 
meant that the disease must be observed by the physician un- 
treated until such periodicity is established, but that value of 
this symptom is in proportion to the reliability of the source 
from which the history is derived. Unfortunately this perio- 
dicity is of little value in estivo-autumnal infections, in which 
the importance and difficulty of diagnosis are greater. 

Quotidian periodicity is not only worthless, but actually 
misleading in the diagnosis of malaria. It is especially in 
septic conditions that mistakes are oftenest made, where not 
infrequently is the rhythmic quotidian succession of chill, 
fever, and sweat mistaken for the metric march of malaria. 
A noted clinician has said that he has rarely seen a case of 
abscess of the liver that had not been drenched with quinine, 
and his experience is not unique in this respect. Malaria is 

256 



DIAGNOSIS 257 

by no means the only condition accompanied with cold, hot, 
and sweating stages, and one or two of these stages are some- 
times wanting in malaria. Abscess of the liver, gall-stone 
disease, tuberculosis, and numerous other diseases may exhibit 
temperature charts closely resembling that of malaria. 

It should be borne in mind, however, that quotidian fever 
in malaria may show tertian or quartan periodicity. Thus in 
double tertian the paroxysms of the first and third days may 
occur at a certain hour in the morning, and those of the second 
and fourth days at a certain hour in the afternoon. Tertian 
periodicity in quotidian fever is valuable from a diagnostic 
view in proportion as the paroxysms on successive days are 
separated from a given hour and those on alternate days 
approach a given hour, or, in other words, as the alternate 
paroxysms approach a forty-eight-hour interval, while the 
accesses on successive days are distant, by more or less, from 
a twenty-four-hour interval. Quartan periodicity in quotidian 
fever rarely comes into consideration in diagnosis on account 
of the relative rarity of the triple quartan infections, the 
promptness with which the microscope decides the matter, and 
the more frequent tendency of one or two of the three groups 
of parasites to sporulate approximately twenty- four hours after 
the last preceding. The course of a double quartan infection, 
two successive fever days followed by a fever-free day, is 
pathognomonic. 

It may be stated as a general rule that tertian and quartan 
periodicity are of importance in diagnosis in proportion to the 
length of the series of paroxysms, since it is not impossible 
that fever on only two days separated by one or two days of 
apyrexia might occur adventitiously from causes other than 
malaria. It is the repetition of this succession that indicates 
malaria, hence the periodicity must be perfectly established. 

The characteristic curve of tertian estivo-autumnal fever is 
probably pathognomonic, but can be obtained in only a small 
proportion of cases in private practice. The clinical course of 
estivo-autumnal infections is of much less value in diagnosis 
than that of tertian and quartan. 

The value of enlargement of the spleen in the diagnosis 

17 



258 THE STUDY OF MALARIA 

of malaria has certainly been overrated. In regions where 
there is little malaria, the endemic index being low, it is proba- 
bly a point of some worth. On the other hand, in malarial 
regions of high index endemicus it is worth much less. It is 
almost valueless in malaria occurring in negroes, as it is infre- 
quently sufficiently enlarged to be palpable, and unless palpable 
is of no diagnostic value. Physicians in malarial regions are 
all familiar with the frequency with which the enlarged spleen 
of the subject of chronic malaria or cachexia complicates other 
diseases. If the physician is sufficiently familiar with the 
patient to know that the splenic enlargement is acute, it be- 
comes a matter of some importance, but the statement of the 
patient as to the former condition of the organ, even when the 
latter is immense, is not always to be relied upon. 

Herpes when present is an aid to diagnosis. The only dis- 
ease in which it occurs with anything like the frequency it 
does in malaria is pneumonia. 

2. The microscopic examination of the blood for the diag- 
nosis of malaria determines the presence or absence of para- 
sites, pigment, and leukocytosis, and the numeric relation of 
the leukocytes. 

Before attempting the diagnosis of malaria by the micro- 
scopic examination of the blood the beginner must become 
thoroughly familiar with the appearance of normal blood and 
with the technic of examination, and he should not rely too 
much upon the result of an examination until he has had con- 
siderable experience with malarial blood. 

While Laveran made his discovery with a one-sixth-inch 
lens, only a one-twelfth-inch oil immersion lens, with appro- 
priate condenser and diaphragm, should be employed, and the 
mechanic stage greatly facilitates the work. Thin slides and 
cover-glasses should be used. 

While stained films of the blood have a wider field of use- 
fulness to the general practitioner than preparations of the 
unstained blood, he should become familiar with the technic 
of each. 

When about to obtain blood to be examined, fresh and 
unstained, several slides and cover-glasses, having been washed 




Fig. 67. — Making the puncture. 





Fig. 68. — Obtaining the bli 




1 



Fig. 69. — Obtaining the blood between slide and cover-glass. 



DIAGNOSIS 259 

thoroughly with soap and water, then with alcohol, should be 
rubbed thoroughly with an old, clean handkerchief and gently 
warmed. While the blood may be obtained elsewhere, the lobe 
of the ear has advantages over other locations ; it is less sensi- 
tive, it being possible to obtain blood from sleeping children 
without awakening them; the instrument and the blood may 
be kept from the view of the patient, an advantage when deal- 
ing with children and nervous persons. More blood is easily 
obtained if desired to make a hemoglobin estimation, blood 
count, or Widal test. The lobe of the ear should be cleaned 
with soap and water, then with alcohol, and should be dried 
thoroughly. It is then grasped between the thumb and fore- 
finger, the latter uppermost. The puncture is made preferably 
with a large straight Hagedorn needle (Fig. 67), and should 
be made quickly to the depth of about one-eighth inch. The 
first one or two drops should be wiped away and one chosen 
which is not too large. 

The cover-glass, held by diagonal corners between the thumb 
and forefinger, or, better, by means of forceps applied to the 
summit of the blood-drop and laid face down upon the slide. 
Care must be taken to touch only the top of the drop and not 
the skin, otherwise the blood smeared upon the cover-glass 
will have begun to coagulate around the margin and will not 
spread freely. It is a common mistake to take too large a 
drop of blood, and if the blood extends to the edges of the 
cover-glass and the center of the film has a ground-glass ap- 
pearance it should be discarded. If the blood does not spread 
freely and evenly it is better not to use pressure, but the cover- 
glass may be gently pushed by the needle applied to its edge. 
Several preparations should be made to insure a good one, 
and each time the ear should be wiped free of blood and a 
fresh drop taken. A rim of vaseline around the edges of the 
cover-glass will preserve the specimen longer. 

As simple as this seems it requires considerable practice to 
obtain films in which the red cells lie side by side and not in 
rouleaux. 

Hayem's method gives better results in the hands of the 
amateur. A square cover-glass is placed upon a slide in such 



20O THE STUDY OF MALARIA 

a manner that one edge of the cover-glass coincides exactly 
with the edge of the slide near its middle. Held rather firmly 
in this position by the thumb and forefinger, the coapted 
edges are applied to the blood-drop when the blood spreads 
evenly between the slide and cover-glass (Fig. 69). When 
the blood has almost reached the opposite edge of the cover- 
glass enough blood has been obtained. Two cover-glasses 
may be used instead of a slide and cover-glass, and when ready 
to be examined one of the cover-glasses cemented at the corner 
or edge to a slide by means of Canada balsam. 

The advantages of dried films over fresh preparations of 
blood are several. Cleanliness of the part from which the 
blood is taken and the size of the drop are not so important. 
This advantage is appreciated by the practitioner who often 
has to make the preparation in the remote corner of an ill- 
lighted cabin. The slides may be laid aside and examined at 
leisure, weeks or even months later. The differential leukocyte 
count can be made on the same slide. 

It is not necessary that the region from which the blood is 
taken should be perfectly clean, but if perspiration is present 
this should be wiped off. The ear is held and the puncture 
made as described for wet films. The slide, held in the right 
hand, is rested against the thumb and forefinger holding the 
lobe of the ear, and gradually lowered until it receives the drop 
of blood near one end. 

The smear may be made by either one of three useful meth- 
ods. The simplest is to hold the slide in the left hand and with 
the right lay the shaft of the needle across the drop of blood 
(Fig. 70). After waiting a few moments for the blood to 
spread out between the needle and the slide, the needle is 
evenly and gradually drawn to the opposite end of the slide. 
Drying the film by rapidly waving it in the air preserves the 
form of the red cells. 

Instead of the needle the end of another slide may be applied 
to the drop of blood (Fig. 71) so that the two slides meet at 
an angle of about 45 degrees ; after waiting for the blood to 
spread along the edge of the slide, the upper slide is then 




Fig. 70. — Making the spread. 




Fig. 71. — Using another slide to spread the blood. 




Fig. *?2. — The cigarette-paper method. 



DIAGNOSIS 261 

drawn to the opposite end of the lower, and the film dried by- 
waving. 

Cigarette paper may be used as follows : Strips about three- 
fourths of an inch wide are cut perpendicularly to the ribs of 
the paper; the end of one of these strips, the original machine- 
cut edge, is applied to the blood-drop near the end of the slide, 
and after a few moments drawn to the opposite end of the 
slide. Other paper may be employed if cigarette paper is not 
available, but does not answer so well (Fig. 72). 

If flies gain access to unstained films they will rapidly devour 
the blood. 

Many staining methods have been proposed to demonstrate 
the malarial parasite in the blood. A common mistake for 
the student to make is to attribute bad results to the stain, and 
to discard a method before he has become familiar with it. In 
no branch of pathology is attention to minute details of technic 
of greater influence upon results, and a method should be 
thoroughly mastered before passing judgment upon it. 

Malarial parasites take basic stains, of which methylene-blue 
is most frequently employed. 

The parent of our modern stains for the malarial parasite 
is that of Romanowsky. The films are made upon cover- 
glasses by obtaining a drop of blood upon the center of one 
cover-glass and laying another diagonally across it. As soon 
as the blood has spread the cover-glasses are drawn apart in 
the same plane, not lifted. When dry the films are fixed by 
immersion in absolute alcohol for ten minutes, or in equal parts 
of absolute alcohol and ether for thirty minutes, or by heating 
in an oven to 150° C, when they are removed and allowed to 
cool. 

The Romanowsky method necessitates two solutions, a satu- 
rated watery solution of methylene-blue, and a 1 per cent, 
watery solution of eosin. Old solutions of methylene-blue give 
better results than recent. The staining solution is mixed 
immediately before use as follows : 

Methylene-blue solution, 2 parts; 
Eosin solution, 4 to 5 parts. 

A precipitate will form, which should not be filtered out, 



262 THE STUDY OF MALARIA 

though the methylene-blue solution may be filtered before mix- 
ing with the eosin if desired. The mixture is poured into a 
watch-glass and the films floated blood side down upon its 
surface for two or three hours. They are then washed in 
water, dried, and mounted. 

Ewing 130 describes Nocht's modification of Romanowsky's 
method as follows : 

1. To 1 ounce of polychrome methylene-blue (Grubler) add 
5 drops of 3 per cent, solution of acetic acid (U. S. P. 33 per 
cent). 

2. Make a saturated (1 per cent.) water solution of methyl- 
ene-blue, preferably Ehrlich's rect. (Grubler), or Koch's, dis- 
solving the dye by gentle heat. This solution improves with 
age, and should be at least one week old. 

3. Make a 1 per cent, solution in water of (Grubler's) aque- 
ous eosin. 

The mixture is prepared as follows : 

To 10 cc. of water add 4 drops of the eosin solution, 6 drops 
of neutralized polychrome blue, and 2 drops of 1 per cent, 
methylene-blue, mixing well. The specimens fixed in alcohol 
or by heat are immersed for two hours, specimen side down, 
and will not overstain in twenty-four hours. The density of 
the blue stain may be varied to suit individual preferences. The 
above proportions need not be rigidly followed, but the poly- 
chrome solution should be accurately neutralized. 

Lcishman's solution combines the fixing and staining proper- 
ties into one solution, the whole process requiring only a few 
minutes. Its manufacture is, however, rather tedious. Two 
solutions are necessary. The first consists of Grubler's 
methylene-blue, 1 part; sodium carbonate, 0.5 part; distilled 
water, 100 parts. This solution is rendered polychrome by 
heating to 65° C. for twelve hours, then exposing to room tem- 
perature for a week or ten days. The other is a 1 : 1000 
watery solution of Grubler's eosin. Equal parts of these solu- 
tions are mixed and allowed to stand for six to twelve hours, 
stirring occasionally. The mixture is then filtered and the 
filtrate thoroughly washed with distilled water and dried. The 
dried filtrate is the stain, and 0.15 gram is dissolved in 100 cc. 




Fig. 73. — Making films upon cover-glasses. 





Fig. 74. — If the forceps are applied to the center of the slide the stain will 

not run off. 



DIAGNOSIS 263 

pure methyl alcohol and kept tightly stoppered. For staining 
a few drops are placed upon the dried, unfixed blood film and 
allowed to stand one-half to one minute, when about twice 
the quantity of water is added, or until the precipitated stain 
is seen floating upon the surface. After five minutes the 
slide is washed in water for about a minute and dried between 
filter paper. 

The most easily prepared of the combined fixing and stain- 
ing solutions, and giving results as satisfactory as any, 
Wright's, is described by the originator as follows : 341 

"This staining fluid is an improvement on one devised by 
W. B. Leishman because it requires only a few hours and an 
ordinary steam sterilizer for its preparation, while Leishman's 
required at least eleven days and the employment of a thermo- 
stat regulated at 65° C. Leishman deserves great credit for 
originating a method of staining blood films and malarial para- 
sites which combines the important 'Romanowsky' staining 
with the great advantages of the methyl-alcohol method of 
Jenner. Wright's stain is applied in the same manner and 
gives the same results. 

"It is preferred to Ehrlich's stain because it does not require 
the difficult and uncertain fixation of the blood film by heat 
and because it gives constantly satisfactory results even in the 
hands of inexperienced workers. 

"This stain makes visible in the blood smear not only all that 
the Ehrlich stain does, but more, for it gives the differential 
Romanowsky staining to mast-cells, blood-plates, certain de- 
generate products in the red corpuscles, and to malarial and 
other protozoan parasites, thus accomplishing at one and the 
same time all that which usually requires the employment of 
several special staining methods separately applied. 

"It is prepared as follows : 

"Dissolve 0.5 gm. of sodium bicarbonate in 100 cc. of dis- 
tilled water, add 1 gm. of methylene-blue (Grubler). Any of 
the methylene-blues of Grubler, known as 'BX,' 'Koch's,' or 
'Ehrlich's rectified,' may be used. It seems to be important 
that the bicarbonate of soda be all dissolved before adding the 
methylene-blue. 



264 THE STUDY OF MALARIA 

"The mixture is next to be steamed in an ordinary steam 
sterilizer at ioo° C. for one hour, counting the time after 
'steam is up.' The heating should not be done in a pressure 
sterilizer, or in a water-bath, or in any other way than as 
stated. This steaming of the alkaline solution of methylene- 
blue effects certain changes in the methylene-blue whereby a 
polychromatic property is given to it, so that the compound 
with eosin, which is later to be formed with it, has the prop- 
erty not only of differentially staining the chromatin of the 
malarial parasite, but also of differentiating and bringing out 
more sharply the nuclei and granules of the white blood cor- 
puscles. 

"When the steaming is completed the mixture is removed 
from the sterilizer and allowed to cool, the flask being placed 
in cold water if desired. When it is cold, without filtering, 
pour it into a large dish or flask and add to it, stirring or shak- 
ing meanwhile, a sufficient quantity of a 1 : 1000 solution of 
eosin (Grubler, yellowish, soluble in water) until the mixture, 
losing its blue color, becomes purple in color and a scum with 
yellowish metallic lustre forms on the surface, while on close 
inspection a finely granular black precipitate appears in suspen- 
sion. This will require about 500 cc. of the eosin solution for 
100 cc. of the alkaline methylene-blue solution. These are 
quantities which are convenient and suitable to employ. 

"The precipitate is collected on a filter and, without washing, 
is allowed to dry thereon. When thoroughly dry dissolve this 
precipitate in pure methyl-alcohol in the proportion of 0.5 gm. 
to 100 cc. of alcohol. This alcoholic solution is the staining 
fluid. It is not necessary to filter it. It will keep indefinitely, 
as will also the dry precipitate. Precautions should be taken 
to keep the alcohol from evaporating, for thus the solution 
may become too saturated and precipitates may form on the 
blood film in the process of staining. If the staining fluid 
deposits such precipitates it should be filtered and a small quan- 
tity of methyl-alcohol added to it. 

"The films of blood, which should be spread thinly, are al- 
lowed to dry in the air. When dry, as much of the staining 
fluid is poured upon the film as the cover-glass will readily 



DIAGNOSIS 265 

hold without draining off. Allow the staining fluid to remain 
in contact with the film for one minute. This chiefly serves 
the purpose of fixing the blood corpuscles. The cover-glass 
is most conveniently manipulated by means of cover-glass 
forceps. . 

"Next add to the staining fluid on the cover-glass distilled 
water, drop by drop, until a delicate scum with iridescent 
metallic lustre forms on the surface. The amount of water 
required will vary with the amount of staining fluid on the 
preparation, but, in a general way, it may be said that six or 
eight drops will be required if a seven-eighth-inch square 
cover-glass is used. The amount of water added must not be 
sufficient to make the fluid transparent. 

"The staining fluid, thus diluted, is allowed to remain on the 
preparation for two or three minutes, during which time the 
real staining of the preparation takes place, and is then washed 
in water. 

"The blood film will now be seen to have a blue or purple 
color, and if examined with the microscope the red blood cor- 
puscles will be seen to be stained blue. 

"The next step is to develop the differential staining of the 
various elements in the preparation. This is done by washing 
the preparation in water — preferably distilled water — until 
the better spread portions of the film appear yellowish or red- 
dish in color. Some tap waters may spoil the staining. If 
desired, the process of differentiation may be readily observed 
by placing the cover-glass film side uppermost on a slide, cover- 
ing it with water, and examining it with the microscope under 
a low magnifying power. The red blood corpuscles, which, 
as before stated, at first have a blue color, will become greenish, 
then yellowish, and finally orange or pinkish in color, depend- 
ing upon the depth of the original staining, which varies with 
the length of time that the diluted staining fluid has been al- 
lowed to act and with the degree of its dilution. 

"The differentiation by washing in water seems to be essen- 
tially a process of decolorization by which some of the blue 
constituent of the dye is removed, for the water that drains off 
from the preparation has a blue color. This differentiation or 



266 THE STUDY OF MALARIA 

decolorization proceeds slowly, and may require one or more 
minutes, depending upon the intensity of the staining and 
upon the tint sought to be obtained in the red corpuscles. 

"It is apparent from the above that with a little experience 
with the method the color of the red corpuscles may be made 
either orange or pink, as the operator desires. When the de- 
sired color is obtained in the red corpuscles the preparation is 
then quickly dried between layers of filter paper and mounted 
in balsam. It is important to stop the decolorization by drying 
the preparation as soon as the desired tint in the red corpuscles 
is obtained, for it may be carried too far. 

"Dried stains on the upper surface of the cover-glass may 
be easily removed with ordinary alcohol. 

"In the light of the foregoing explanations the following 
summary of the method of staining blood films will be intelli- 
gible : 

"i. Make films of the blood, spread thinly, and allow them 
to dry in the air. 

"2. Cover the preparation with the staining fluid for one 
minute. 

"3. Add to the staining fluid on the preparation sufficient 
water, drop by drop, until a delicate iridescent, metallic scum 
forms on the surface. Allow this mixture to remain on the 
preparation for two or three minutes. 

"4. Wash in water, preferably in distilled water, until the 
film has a pinkish tint in its thinner or better-spread portions 
and the red corpuscles acquire a yellow or pink color. 

"5. Dry between filter paper and mount in balsam. 

"The preparations retain their colors as long as any prepara- 
tion stained with aniline dyes. 

"Unstained blood films may be kept for some weeks without 
impairment of their staining properties. Films months old 
will probably not give good results. 

"The red cells are orange or pink in color. Polychromato- 
philia and punctate basophilia or granular degeneration are well 
brought out. The nucleated red cells have deep-blue nuclei 
and the cytoplasm is usually of a bluish tint. 

"The lymphocytes have dark purplish-blue nuclei and rob- 



DIAGNOSIS 267 

in's-egg-blue cytoplasm, in which a few dark blue or purplish 
granules are sometimes present. 

"The polynuclear neutrophilic leukocytes have a dark blue 
or dark lilac-colored nucleus, and the granules are usually of 
a reddish-lilac color. 

"The eosinophilic leukocytes have blue or dark lilac-colored 
nuclei. The granules have the color of eosin, while the cyto- 
plasm in which they are imbedded has a blue color. 

"The large mononuclear leukocytes appear in at least two 
forms. Each form has a blue or dark lilac-colored nucleus. 
The cytoplasm of one form is pale blue, and of the other form 
is blue with dark lilac or deep purple-colored granules, which 
are usually not so numerous as are the granules in the poly- 
nuclear neutrophilic leukocytes. 

"The mast-cells appear as cells of about the size of poly- 
nuclear leukocytes, with purplish or dark blue-stained, irregu- 
lar-shaped nuclei, and with cytoplasm, sometimes bluish, in 
which numerous coarse spheric granules of variable size are 
imbedded. These granules are of a dark purple color and may 
appear almost black. 

"The myelocytes have dark blue or dark lilac-colored nuclei 
and blue cytoplasm, in which numerous dark lilac or reddish 
lilac-colored granules are imbedded. In leukemia more color 
differences are brought out among the leukocytes than by the 
ordinary methods of staining. 

"The blood-plates are well stained. In the best preparations 
they appear as round or oval, very pale blue bodies with smooth 
contour, containing many small dark lilac or blue-stained 
granules. In many instances, however, only the deeply stained 
granules in their substances are visible. They are usually of 
a diameter of one-third to one-half of that of a red blood 
corpuscle. Frequently they occur in groups or masses, and at 
first sight may be regarded as precipitates." 

The powdered stain keeps well, but the solution after a 
time tends to lose its blue-staining property, hence small quan- 
tities only of the solution should be prepared. If too intensely 
blue at first some old stain may be added until the desired tint 
is obtained. Films prepared upon slides are more easily dealt 



268 THE STUDY OF MALARIA 

with than those upon cover-glasses. The cedar oil is dropped 
directly upon the stained film. 

The examination should be protracted for thirty minutes 
before being pronounced negative. While parasites, if present, 
are usually found within five or ten minutes, it is not uncom- 
mon to detect the first organisms after a search of twenty to 
thirty minutes. 

Cedar oil may be removed from the film by wiping gently 
with a soft cloth moistened with xylol. 

The "thick film process" is occasionally useful where the 
parasites are very scanty. The blood is smeared upon the 
slide in a much thicker layer than for other methods. After 
drying, a little distilled water is added and allowed to remain 
fifteen minutes, which causes the dissolution of the hemoglobin. 
After drying again the film is stained by one of the usual 
methods. While the outlines of the red cells are still visible, 
the cells are transparent and parasites may be detected, though 
lying under several cells. The advantage of this method is 
that a much larger volume of blood may be examined in a 
shorter space of time than is the case with the thin film. 

Flagella are much more easily demonstrated in the gametes 
of the estivo-autumnal than of the tertian and quartan para- 
sites. The crescent becomes oval and then spheric before 
exflagellation is observed. To encourage this process the 
method of Stephens and Christophers 118 is most practical. A 
number of rather thick drops of blood are placed upon a series 
of slides. The slides are then inverted, with the hanging drops 
over holes cut in blotting paper, moistened with water, and 
spread on a pane of glass. A series of moist chambers is thus 
made. A slide is removed at intervals of five minutes, the 
blood spread in the usual manner and stained. Exflagellation 
is also observed in preparations of fresh blood. The warm 
stage, breathing upon the specimen, and the addition of a little 
water are recommended to hasten the process. 

Sources 'of Error. — In the examination of blood for mala- 
rial parasites there are several objects which may mislead. Pit- 
falls are probably more common in fresh blood than in stained 
films. 



DIAGNOSIS 269 

Vacuoles and retractions of hemoglobin in red cells of fresh 
preparations are delusive and not infrequently mistaken for 
the young hyaline forms of the parasite. They are most com- 
mon in the center of the cell, while parasites are found in any 
portion. Vacuoles are highly refractive, having well-defined, 
clear-cut edges ; the margins of the parasites are dim and fade 
gradually into the substance of the red cells. The vacuoles 
may show slight changes of form, but do not possess true 
ameboid motion nor pigment. While the vacuoles are per- 
fectly clear, the parasites show a slight opalescence. In stained 
specimens areas which do not take the stain may deceive. 
These areas may be of circular form in the center of the cell, 
or of ring form surrounding the center, or may be oval, horse- 
shoe shaped, crucial or irregular. When present they are apt 
to be abundant in some portions of the film and entirely absent 
elsewhere. 

Crenations of red cells may present a hyaline appearance 
somewhat resembling an ameboid parasite. Their nature may 
be determined by changing the focus. 

Bent or buckled corpuscles occasionally resemble crescents. 
The absence of pigment and the size of corpuscle should, how- 
ever, enable a distinction. Overlapping of the corpuscles may 
produce a ring or crescent appearance which deceives the be- 
ginner. 

The object in stained spreads which proves most deceiving 
to the inexperienced is probably the blood platelet. These cor- 
puscles may lie upon or within the red cells, in the center, 
near the periphery, or only partially enclosed by them. They 
are from one-seventh to one-half the size of a red blood-cell, 
and are round, oval, or elongated in shape. They are often 
of mulberrry shape and reticular structure, and, with the 
Romanowsky class of stains, approach more nearly purple or 
lilac than the characteristic blue of the parasites. The margin 
is surrounded by a pale or unstained area resembling a halo. 
There is, of course, an absence of pigment and chromatin. 
Occurring in groups, as it frequently does, it has not rarely 
been mistaken for a sporulating body, and isolated for a free 



270 THE STUDY OF MALARIA 

spore. Bodies resembling free spores should, however, be 
disregarded for diagnostic purposes. 

The nuclei of nucleated red corpuscles may be mistaken for 
parasites, but this should rarely occur if the morphology and 
staining reactions of both bodies is borne in mind. 

Cabot 342 and others have found in the blood of patients 
afflicted with pernicious anemia, leukemia, and lead poisoning 
ring-shaped bodies occurring within the red cells and not unlike 
malarial parasites. Their origin or significance is not known, 
but they are thought to represent nuclear remains. 

Pigmented leukocytes have been mistaken for parasites, but 
the ameboid motion of the former in fresh specimens and the 
staining reactions in dried films should prevent confusion. 

Hemokonia, or blood-dust, may be confused with free spores. 
They are small, highly refractive, micrococcus-like bodies aver- 
aging one-half micron in diameter and possessed of very ani- 
mated motion. . As stated, free spores should not be sought for 
diagnosis, and bodies resembling them should be ignored. 

Extraneous dirt, leukocyte granulations, and stain precipi- 
tates must be carefully distinguished from pigment. 

The amateur in examinations of malarial blood is apt to be- 
come decidedly discouraged, even when he has satisfactorily 
mastered the technic in the laboratory. Most students gain the 
impression that all that is necessary to find the parasites is to 
locate a malarial subject with any form of the disease and 
obtain the necessary blood at any stage of parasitic develop- 
ment, to stain it properly, and to inspect it under a high-power 
lens. Usually this' is what he has been taught by text-books 
and by teachers, and when he fails to detect the characteristic 
organisms in undoubted cases of malaria he is disgusted. The 
results of such teaching throw discredit upon a discovery whose 
practical importance is unsurpassed in modern medicine. 

To estimate the value of a report on the result of micro- 
scopic examination of the blood for malarial parasites it is 
always desirable to know something of the experience of the 
examiner. In addition to competence and proper technic there 
are several factors which influence the result of the examina- 
tion for parasites. The most important of these are : (a) the 



DIAGNOSIS 271 

previous administration of quinine; (b) the stage of develop- 
ment of the organisms; (c) the stage of the disease; (d) the 
type of infection; (e) race; (/) locality, and (g) individual 
circumstances. 

(a) The previous administration of quinine, even in small 
quantities, renders it almost useless to examine the blood with 
the expectation of finding parasites. Even where the quantity 
of the drug is insufficient to have any effect on the symptoms, 
it will ordinarily cause a disappearance of the parasites from 
the peripheral circulation. The half-poisoned parasites which 
persist in some instances are frequently unrecognizable with 
reference to type. 

(b) The quartan parasite is nearly evenly distributed in all 
its phases, from the youngest form to the sporulating body, 
throughout the superficial and deep circulation. Hence, when 
dealing with this type it makes little difference at what period 
the blood is examined. But with the estivo-autumnal organism 
it is only the early stages, the small rings, that are observed 
with any degree of frequency in the peripheral blood, and if 
the examination is made when the parasite has reached a later 
stage of development it will probably be missed. Instead of 
resembling the quartan parasite in habit of distribution it seems 
to imitate its more distant relative, the Leishman-Donovan 
parasite. Later phases of the simple tertian hematozoon are 
less commonly found in examinations of the peripheral blood 
than are those of the quartan, but are much more frequently 
observed than those of the estivo-autumnal. Sporulating 
bodies of the quartan type are not uncommon in the cutaneous 
blood, while those of the tertian are much less common and 
those of the estivo-autumnal extremely uncommon. 

The frequency with which crescents are detected varies with- 
in the broadest confines. In the experience of some they are 
rare, while other observers note them frequently in estivo- 
autumnal infections. Tertian gametes are not rarely observed 
in the blood of the superficial circulation, while quartan gametes 
are scarcely found. 

(c) In acute untreated malaria the parasite can be detected 
at some stage of its growth in almost 100 per cent, of cases. 



272 THE STUDY OF MALARIA 

If not found at the first examination, as frequently occurs, 
subsequent searches are usually successful. On the contrary, 
in chronic malaria the parasites are far from constant during 
* the stage of latency, and prolonged search may fail to reveal 
them during the relapse. Parasites are often absent from the 
peripheral blood of malarial cachectics. In the paramalarial 
syndrome, hemoglobinuric fever, the parasites, if present before 
onset, afterward disappear in the majority of cases. 

(d) The behavior of the different kinds of parasite in their 
various stages has been referred to. As a rule, the quartan 
parasite is most certainly found on first examination, the estivo- 
autumnal least so, on account of its habit of resorting to the 
deep circulation when approaching maturity. It is very unfor- 
tunate for rapid diagnosis that the estivo-autumnal parasites 
are less readily detected than those of the benign infections, 
but, fortunately, are usually easily found in pernicious cases of 
estivo-autumnal infection. 

(e) That malarial parasites are found less frequently and 
in smaller numbers in the superficial circulation of negroes with 
malaria the writer is convinced, though the difference is slight. 
This opinion is confirmed in part by the observations of Kulz, 247 
who found malarial parasites much less frequently in his negro 
malarial patients than in white. 

(/) Along the Northern borders of malarial distribution the 
parasites are probably more readily detected. This may be 
accounted for partially by the greater relative frequency of 
simple tertian infections. Whether the more northern negro 
shows the same scanty distribution of parasites in the peripheral 
blood as manifested by his southern brother the writer has no 
means of determining. It is surprising with what frequency 
crescents are found in higher latitudes in the blood of patients 
moving from highly malarial localities where crescents are not 
so frequently observed. Whether this is a conservative measure 
related to the relative rarity of anopheline mosquitoes cannot 
be stated positively, but it is known that the life histories of 
animals are, in some instances, peculiarly interdependent, espe- 
cially in the case of parasite and host. 

(g) Why it is that in certain unquestionable cases of malaria 



DIAGNOSIS 273 

which have received no quinine and in which every condition 
seems favorable to finding the parasites prolonged and repeated 
examination shows none is not known, but such cases are some- 
times encountered. 

As before said, where the specific can be withheld and re- 
peated examinations made by a competent microscopist if not 
found at the first examination, the parasite may be found in 
almost 100 per cent, of cases of malaria. The question, which 
is of the utmost practical importance to the physician, arises : 
In what proportion of cases is the parasite to be found at a 
single examination? On this depends in great measure the 
practical value of Laveran's discovery, for in not a few cases 
in general practice for reasons of convenience the examination 
cannot be repeated, in others in which the diagnosis seems 
more or less clear urgent symptoms are demanding the specific. 
The two factors which more than the others influence the result 
are whether or not the patient has received quinine and the 
phase of parasitic development attained when the blood is with- 
drawn for the examination. Neither of these factors is always 
within the control of the physician who desires to make a diag- 
nosis upon examination of the blood taken when the patient 
first comes under his observation. Since a very large proportion 
of the malaria of the land is treated by country doctors, the 
practical value of a diagnostic test is largely in proportion as 
it is applicable by them. 

With reference to the number of cases in which the parasite 
can be found at the first examination the writer will state his 
experience. From a record kept of the number of malarial 
cases which had taken quinine in some form before coming 
under observation it was learned that this reached something 
over 50 per cent, of the total number of cases treated. The 
diagnosis in these cases was obviously based upon the clinical 
history and the therapeutic test, since the search for parasites 
in the blood of persons having received quinine is so discourag- 
ing that this has not been done in routine work, but only in 
special cases. Allowing for errors in diagnosis might reduce 
this number to 50 per cent. A specimen of blood was always 
taken from malarial patients who had not recently received 

18 



274 THE STUDY OF MALARIA 

quinine when they came under observation for the first time, 
irrespective of the stage of the access. The blood from frank 
cases only has been included, no cases of atypic or latent mala- 
ria or of cachexia figuring in the result. Parasites were found 
in approximately two-thirds of the cases and the examination 
was negative in about one-third. No difference as to clinic 
course, severity, or the efficacy of quinine could be detected 
between the cases in which parasites were found and those in 
which none were observed. From this experience may be in- 
ferred that in localities in which half of the malarial subjects 
take quinine in some form before consulting a physician the 
parasite can be detected at a single examination of the periphe- 
ral blood taken at random with respect to the stage of parasitic 
growth in approximately one-third of the cases only. The 
prevalence of self -medication with quinine products depends 
largely upon local custom and upon the energy of the patent 
medicine industry. 

The experience of the writer being somewhat at variance 
with the conventional text-book teaching, he feels it incumbent 
upon him to cite the experience of others in this matter of the 
most vital interest. 

Craig 70 says, "Often if the blood be examined but once none 
at all will be found." 

Fornario 343 observes that the parasites are missed with ex- 
treme frequency, and Soliani, 147 in an analysis of 612 cases 
under his care, says that in many cases the first examination 
was negative. 

McElroy 344 says, "I have been struck with the frequency with 
which I have been unable to find parasites in cases where I 
am strongly impressed with the malarial nature from the 
clinical history." 

Plehn 345 states that the parasites are frequently lacking in 
the malaria of natives, or at least they are not found in the 
peripheral blood, where the temperature curve is typic and 
pigmented leukocytes indicate malaria. 

The experience of Ewing 27 at Camp Wikoff is interesting. 
"In the 605 cases of malaria the plasmodia were found in the 
blood in 335 cases, while in 270 cases the diagnosis was based 



DIAGNOSIS 275 

upon the clinical history and the discovery in the blood of evi- 
dences of malarial infection. The evidences of malarial infec- 
tion in the blood consisted ( 1 ) usually in the presence of intra- 
cellular bodies so much affected by quinine that their exact 
type could not be positively determined; or (2) in the presence 
of typic pigmented leukocytes; or (3) in chronic cases of dis- 
tinct clinical character in the presence of marked anemia." 

Leonard Rogers, 86 than whom there is no more competent 
observer, says: "As long ago as 1896 I showed from an ex- 
amination of 100 cases of consecutive malarial fever before the 
administration of quinine that in only one-third of them could 
the malarial parasite be found by means of a prolonged search 
of a single blood film." 

Delaney's 346 experience is even more disheartening. He con- 
cludes : "I think that I shall be supported by most competent 
observers in India that this (17 per cent. ) about represents the 
percentage of success in finding malarial parasites in the mala- 
rial fevers of India at a single examination, and on this point 
both text-books and writers on the subject are, I consider, very 
misleading." 

Such quotations from practical workers and keen observers 
could be multiplied, but could add no further weight to the 
authority of those cited. 

The above statements are not meant to cast the slightest 
doubt upon the etiologic role of the parasite of malaria, or its 
presence in every case of acute untreated malaria, or its great 
diagnostic value under certain circumstances, but are intended 
to demonstrate that the detection of the parasite is subject to 
several conditions. In probably no other disease, associated 
with a pathognomonic sign which can be elicited in almost 100 
per cent, of cases, is its detection so dependent upon conditions 
beyond the control of the physician. 

What is the value of a positive result of examination of the 
blood for malarial organisms? This parasite is thoroughly 
established as the sole cause of malaria, and its pathogenic 
reputation has never been marred by rumors of etiologic asso- 
ciation with other diseases, but is the parasite, when present, 



276 THE STUDY OF MALAEIA 

responsible for the symptoms which instigate the blood ex- 
amination ? 

In localities where a considerable per cent, of the inhabitants 
carry malarial germs in their blood without showing malarial 
symptoms it is manifestly possible that parasites might be 
found in the blood of such inhabitants during the course of 
other ailments. And such is actually the case in certain regions 
with a very high endemic index, to such an extent, indeed, that 
the widely experienced Albert Plehn," in Cameroon, declared 
that the presence or absence of malarial parasites in the blood 
of the West African coast negro is of no diganostic value. 

In cases of coma in which malarial parasites are detected 
and which give a history of exposure to violent heat or of the 
abuse of alcohol, it is not infrequently difficult to determine the 
part played by the parasite. In cases of coma accompanied by 
malarial parasites in the blood and albumin and casts in the 
urine the diagnosis may be obscure. Fever occurring during 
the puerperium in subjects of former malaria will make the 
thoughtful physician uneasy for a short while at least, even if 
parasites are found on blood examination. 

These are mainly problems, however, which are involved in 
other fields of diagnosis and serve to impress the fact that com- 
plications must be excluded or, if found, weighed. While 
these contingencies should not be lost sight of, in the immense 
majority of cases in this country active forms of the malarial 
parasite detected in the blood are responsible for the symptoms 
which bring the patient under the care of the physician or 
which prompt the physician to make the examination. 

It will be noted that the word active is emphasized. What, 
then, is the value to be attached to the discovery of gametes 
alone ? 

Formerly it was believed that the sole function of these pecu- 
liar bodies was the perpetuation of the species through the 
mosquito cycle. Under this limited view the detection of 
gametes alone was on a diagnostic par with anemia and spleno- 
megaly, sequelae of malaria, and not necessarily proof of exist- 
ing malaria, even latent. Since it has become known, however, 
that under certain not well understood conditions the macro- 



DIAGNOSIS 277 

gametes can immediately, by the process of parthenogenesis, 
give rise to pyrogenic parasites without undergoing the mos- 
quito cycle, our views must be modified, and these forms must 
be regarded clinically as the parasites of latent malaria. Rela- 
tive to active malaria, they may be looked upon as evidences 
of past and potential, but not necessarily of present, active 
malaria. 

In regard to the number of parasites in a given film of blood 
the following classification applies to estivo-autumnal infec- 
tions : 

Abundant when there is an average of two or more parasites 
to each field of the microscope ; they are detected immediately. 

Moderately numerous when present in only one of several 
fields ; found after a few minutes' search. 

Scanty when only a few parasites are detected in the entire 
film, as commonly prepared, aften ten to thirty minutes' search. 

While there are many cases of estivo-autumnal infection in 
which the parasites are scanty, large numbers of estivo- 
autumnal parasites are occasionally observed in the peripheral 
blood, especially of pernicious cases. As many as 75 per cent, 
of the red cells have been found infested in several cases re- 
ported, and Rogers 44 mentions a rapidly fatal case in which 
the blood showed more parasites than erythrocytes. 

What is the diagnostic value of a negative result ? 

The writer can by no means agree with those who maintain 
that such a result positively excludes a diagnosis of malaria. 
The failure to find parasites in the blood of a single film taken 
without reference to the period of the paroxysm, while of some 
value, is not conclusive, and if the patient has recently received 
quinine is absolutely worthless. On the other hand, if the blood 
of a patient who has not recently taken quinine be examined 
repeatedly by a competent person with the result that no para- 
sites are found, it is very strong evidence against malaria. 
The diagnostic value, then, of a negative finding depends upon 
the presence or absence of the conditions which have been 
enumerated, the chief of which is the administration of quinine. 

When the examination of the peripheral blood is negative 
puncture of the spleen has been advised, as the parasites in all 



278 THE STUDY OF MALARIA 

stages are easily detected in the blood of this organ. This pro- 
cedure, however, is attended with some degree of danger, espe- 
cially of hemorrhage, and should be resorted to only in cases 
where an immediate diagnosis is imperative. It has been esti- 
mated that the mortality of aspiration of the spleen is i~y 2 per 
cent. 158 Many fatalities have resulted in India recently from 
this method of obtaining blood for the study of the Leishmann- 
Donovan parasites. 44 When decided upon the following pre- 
cautions should be observed : An aspirating syringe or even 
an ordinary hypodermic syringe may be employed. A flexible 
connection between needle and nipple, such as comes with the 
regular antitoxin syringe, is valuable to prevent laceration of 
the capsule of the spleen in the event of sudden respiratory 
movements. Both the syringe and the site of injection should 
be rendered sterile. Cutaneous sensation may be deadened with 
cocaine or with ethyl chloride. The patient should be in- 
structed to hold the breath on deep inspiration, and the spleen 
should be steadied against the ribs and diaphragm. The needle 
should be inserted deeply and when the syringe is half filled 
should be partially withdrawn, then filled, to obtain the blood 
from two points. The operation should be performed quickly, 
that the patient may not have to breathe during the process, 
as the danger of laceration is thereby increased. Afterward 
the cutaneous puncture should be sealed with collodion, the 
patient kept at rest in the recumbent position for twenty-four 
hours, and cold applications placed over the region of the 
spleen. A dose of calcium chloride administered half an hour 
before the procedure might lessen the tendency to hemorrhage. 

Upon failure to discover parasites in the blood there are two 
other blood signs which must be considered. These are the 
presence of pigment and a relative increase in the large mono- 
nuclear leukocytes. These signs are termed subsidiary evi- 
dences of malaria, because, being secondary in diagnostic im- 
portance to the parasites, they are generally called upon only 
in the absence of the latter. 

Melanin is pathognomonic of malaria, and its presence is 
not contingent upon the stage of development of the parasites 
or upon the previous administration of quinine. Theoretically, 



DIAGNOSIS 279 

therefore, it should be of the greatest significance in the diag- 
nosis of malaria. There are, however, certain circumstances 
which detract from its practical value. Free pigment, or that 
lying upon the red blood-cells, should be ignored in the diag- 
nosis, as it cannot be distinguished from adventitious detritus. 
Within the large mononuclear leukocytes, the leukocytes in 
which it is most frequently found, it must be carefully distin- 
guished from the minute pigment-like granulations which may 
occur normally in these cells to the number of one, two, or 
three to each cell. This requires a considerable degree of 
experience and deceived a no less accurate observer than Vin- 
cent. 347 Coarse granules of pigment are much more readily 
recognized, especially in fresh blood. In stained films precipi- 
tates may prove very confusing. Pigment may persist for two 
or three days after the last paroxysm in tertian and quartan 
infections, and for a much longer period in estivo-autumnal. 
It is more valuable as a diagnostic sign of chronic malaria than 
of acute. 

The second subsidiary sign of malaria, a relative increase 
of the large mononuclear leukocytes, is under some conditions 
a valuable aid to a diagnosis. The proportion of large mono- 
nuclear elements in the differential count is modified by certain 
factors which detract somewhat from its value. 

In early childhood there is normally an increase of mono- 
nuclear leukocytes, hence this sign need not be sought for in 
the malaria of young children. 

As with other diagnostic evidences of malaria, this sign is 
unfortunately more constant and more marked in tertian and 
quartan infections than in estivo-autumnal. 

The increase of the large mononuclear leukocytes in malaria 
is generally in inverse proportion to the height of the temper- 
ature, being most decided in the interval and may be absent 
during pyrexia. An increase may be wanting also early in first 
attacks. 

In making the differential count the leukocytes lying in the 
middle third of the film should be counted and the slide moved 
from side to side and not from end to end. If the colorless 
cells are calculated at random or only near the ends of the 



280 THE STUDY OF MALARIA 

smear it will make quite a difference, particularly in the relation 
of the small lymphocytes to the large mononuclears, and 
this relation is significant. It is an interesting experiment 
to make and compare differential leukocyte counts at both the 
beginning and the end of the spread. For accuracy at least 
500 cells should be counted, though 250 give a fairly correct 
estimate. 

Perhaps the chief difficulty in the procedure is the almost 
arbitrary distinction between the small mononuclear and the 
large mononuclear leukocytes. An investigation of the litera- 
ture upon the subject convinces that the definitions of the large 
mononuclear leukocyte are essentially different. Furthermore, 
since the chief difference, size, is one of degree only, it is 
obvious that there is much room for error in the application 
of any one of these definitions and that it requires a good deal 
of experience to become skilful in the employment of this 
diagnostic measure. 

When there is evidence of leukocytosis the differential count 
alone must not be relied upon, since an absolute increase may 
exist under these circumstances when the differential count 
will show only a small per cent. Here the absolute count must 
be made also. 

In differentiating malaria from typhoid fever the differential 
count is of value only in the first two weeks of a fever, since 
after that time the relative proportions of the leukocytes are 
similar in the two diseases. 

Notwithstanding its difficulties, the differential leukocyte 
count made by an experienced examiner may render important 
aid in the diagnosis of malaria where the parasite cannot be 
detected, and a mononuclear leukocytosis reaching 15 per cent, 
must be regarded as strong evidence of malaria. 

Besides the presence of pigment and a large mononuclear 
increase there is another point ascertained by microscopic ex- 
amination of the blood, this is the presence or absence of 
leukocytosis. Between malaria and typhoid fever this point 
has no differential value, and it will be remembered that a 
leukocytosis is frequent in pernicious malaria. It is, however, 
in septic conditions which sometimes so closely resemble mala- 



DIAGNOSIS 28l 

ria in which a marked leukocytosis may serve to exclude 
malaria. 

3. The Therapeutic Test. — The diagnostic value of the 
therapeutic test has been known since the days of Torti, 
though neither its value nor its limitations are yet widely real- 
ized. On the one hand, there are theoretic and ultrascientific 
writers, apparently valuing a microscopic diagnosis more highly 
than human life, who advocate withholding the specific indefi- 
nitely until the parasite may be found. On the other hand, 
there are physicians who continue the administration of quinine 
in heroic doses for days, or even weeks, in fevers which do 
not show the slightest susceptibility. 

Here diagnosis and treatment meet very closely, the former 
encroaching somewhat upon the field of the latter, the diagnos- 
tic test often becoming a therapeutic and life-saving measure. 
The therapeutic test is of especial value in cases which have 
already had insufficient quinine, thereby causing only the dis- 
appearance of the parasites from the superficial circulation and 
distortion of the fever curve. In these cases it has at least as 
much standing in clinical medicine as antisyphilitics in obscure 
cases thought to be syphilis or antitoxin in cases of suspicious 
angina in which a bacteriologic examination is impossible. 
When properly applied it can hardly be productive of harm. 

A fever which resists quinine is not a malarial fever. In 
order to test the resistance of a fever to quinine the drug must 
be continued for a sufficient length of time and in proper doses 
at suitable intervals, and, what is most important, it must be 
absorbed. 

The maximum period of resistance of malaria to quinine is 
ordinarily stated as four days. As far as the writer's observa- 
tions go, they tend to show that in many cases the fever is 
broken by the end of thirty-six hours, in at least half the cases 
in forty-eight hours, and in three-fourths the cases in sixty 
hours. It is highly probable that in cases of malaria persisting 
longer than four days the specific is not being absorbed. A 
case is recalled in which the fever continued notwithstanding 
the administration in capsules of 24 grains of a soluble salt of 
quinine during the twenty-four hours for nearly six days. 



282 THE STUDY OF MALARIA 

Parasites having been found before the quinine was begun, the 
drug was then given in solution, when the fever responded dur- 
ing the seventh day. There had been no evidences of cin- 
chonism until the solution was employed. Cinchonism, how- 
ever, is not a guide in the employment of the therapeutic test; 
the specific is directed toward the parasites and not toward 
the patient, and patients manifest various degrees of sensitive- 
ness toward quinine. 

Owing to the conditions under which the therapeutic test is 
usually employed it is better to use moderate doses at regular 
intervals during both day and night. Three or 4 grains every 
three hours are sufficient. Pills and tablets of quinine should 
never be relied upon ; the result may be not only misleading but 
dangerous. Capsules, if fresh, are usually satisfactory; a few 
pin punctures in each end aids solution. Where the fever per- 
sists and there is reason to believe that the medicine is not being 
absorbed it should be given in solution or even intramuscularly. 

In connection with the therapeutic test the law of Treille 304 
is interesting-. It may be stated as follows : 

In malarial fever quinine given in a single proper dose at 
the beginning of a paroxysm does not influence that paroxysm, 
but always suppresses the following for a minimum period of 
five days. Designating the day upon which quinine is admin- 
istered as 1, the minimum duration of apyrexia as 5, and the 
day of recurrence as 1, the formula may be graphically repre- 
sented as 1-5-1. In the case of quotidian and quartan fevers 
the duration of apyrexia is often a multiple of 5. The formula 
is, then, 1-1115-1. Treille regards as a proper dose: for quartan 
fever, 25 centigrams; for quotidian, 2.5 grams, and for tertian, 
2 grams. 

The writer cannot vouch for the details of these propositions, 
but the general principle has ample support. In thorough ac- 
cord are the recently recorded and accurate observations of 
Cohen, 305 who ascertained that a single subcutaneous injection 
of 15 grains of quinine and urea, given preferably during the 
paroxysm or shortly after, produced an apyretic period of 
approximately six and a half days or approximately thirteen 
days. 



DIAGNOSIS 283 

This period of apyrexia following a single dose of quinine 
corresponds closely to the parthenogenetic cycle. The con- 
quest of the schizonts seems to be a signal for the macro- 
gametes to lay aside the conventionality of slow sexual repro- 
duction and to conscript recruits rapidly by parthenogenesis. 

Not every fever which discontinues after the administration 
of quinine can be considered malarial, since such an occurrence 
is occasionally coincidental. Furthermore, it is well known that 
quinine has no little antipyretic influence upon certain condi- 
tions, particularly septic. 

It is probably superfluous to say that the diagnosis of malaria 
does not always consist alone in the mere mechanic application 
of a single test, but that in some cases the keenest clinic judg- 
ment is required. Of the several diagnostic signs which we 
possess each is valuable and each has its limitations. 

It should be a routine practice to take a specimen of blood 
from each fever patient. 

In dealing with a disease in which the blood examination 
affords pathognomonic evidence and for which we possess a 
specific the dilemma is often faced, where the examination of 
the first specimen of blood is negative, of having to decide 
whether it is best to wait a few hours for an absolutely certain 
diagnosis or to take advantage of every hour and begin the 
treatment immediately. If quinine has already been taken the 
chances are that further examinations would also be negative, 
and the better course would be to proceed with the specific. 
If quinine has not already been taken and the symptoms are 
not urgent the case may be treated symptomatically for a little 
while, during which time the blood is examined at appropriate 
intervals. 

In hospital practice the practical value of the blood examina- 
tion for malarial parasites is inestimable; in general practice, 
especially in the rural districts, its value is more limited. In 
general practice, especially in the country, the therapeutic test 
is of great value; in hospital practice it is less often justifiable. 



284 THE STUDY OF MALAR A 

DIFFERENTIAL DIAGNOSIS 

The differential diagnosis between the malarial infections 
can best be made with the microscope. In only one type of 
infection, the quartan, either single or double, can the differ- 
ential diagnosis be made clinically with certainty. 

The differentiation of chronic malaria from cachexia is 
sometimes very difficult, the relation being one of disease entity 
and sequel, and the difference sometimes one of degree only. 

The diagnosis of latent malaria must be based solely upon 
the detection of parasites in the blood. Basophile granulation 
of the red cells and urobilinuria cannot be relied upon as evi- 
dences of latent malaria. 

Abscess of the Liver. — Septic conditions are very often 
diagnosed as malaria ; this is especially true of hepatic abscess. 
There are two classes of cases of abscess of the liver that may 
be difficult at first examination to distinguish from malaria; 
first, where the local symptoms are absent or not well defined ; 
second, where there is enlargement of both liver and spleen and 
a history of both dysentery and malaria. The fact that these 
patients have usually been drenched unsystematically with 
quinine may complicate the diagnosis. In typic cases of hepatic 
abscess there is usually a history of dysentery, and amebse may 
be present in the feces. There is usually a dragging pain in 
the liver, sometimes referred to the right shoulder, increase of 
liver dulness, and tenderness on pressure. The spleen is not 
necessarily enlarged. The temperature does not often rise 
high, and there is apt to be profuse perspiration, especially 
during sleep. On microscopic examination of the blood there 
is usually a leukocytosis to be found, though this is wanting 
in a few cases, and its absence should not be taken to exclude 
abscess. There are neither parasites, pigment, nor a relative 
increase of the large mononuclear leukocytes. Exploratory 
aspiration is valuable in some cases. Jaundice is a very variable 
symptom and may be misleading. 

Infective endocarditis may present periodic paroxysms of 
chill, fever, and sweat. The physical examination of the heart 
and the microscopic examination of the blood should establish 
the diagnosis. 



DIAGNOSIS 285 

Puerperal Septicemia. — Women who have had malaria 
during pregnancy are prone to suffer relapses during the puer- 
perium. In this condition malaria is not infrequently atypic : 
the first or third stages of the paroxysm are sometimes lacking 
and complete intermission of temperature is often wanting. 
The following may serve to differentiate typic cases of malaria 
and puerperal sepsis : 

Malaria. Puerperal Septicemia. 

Onset from a few hours to twenty- Rare after the fifth day. 

one days after labor. 

Often a history of malaria. Malarial history usually absent. 

Temperature curve more or less Irregular. 

typic. 

Symptoms decline with temperature. No relation between symptoms and 

temperature. 

No local symptoms. Local symptoms present. 

Blood examination positive. Negative. 

Therapeutic test positive. Negative. 

The so-called urethral fever may be accompanied by parox- 
ysms somewhat resembling those of malaria. The writer has 
recently seen a case in which the introduction of a steel sound 
every other day was accompanied for a short time by corre- 
sponding paroxysms not due to malaria. The differentiation 
from malaria should present no difficulties. 

Perinephritic abscess, pyelitis, cholecystitis, and other septic 
processes may be associated with fever which bears a more or 
less close resemblance to that of malaria. Local symptoms, the 
blood examination, and the therapeutic test rarely leave the 
diagnosis in doubt but a short while. 

Typhoid Fever. — Since Laveran's discovery and since the 
knowledge of the prompt efficacy of quinine in malaria and the 
value of the Widal reaction have become thoroughly established 
mistakes in the diagnosis of typhoid fever and malaria should 
be relatively infrequent. This is unfortunately not the case. 
Witness the lesson of the Spanish-American War : Of 20,738 
cases of typhoid fever occurring in the American army, 10,428, 
or 50.27 per cent., were correctly diagnosed by regimental or 
hospital surgeons. Most of the remainder were called malaria ; 
ten thousand mistakes in one season, and the board of inves- 
tigation concludes that in recognizing about half the cases of 



286 THE STUDY OF MALARIA 

typhoid fever the army surgeon probably did better than the 
average physician throughout the country does in his private 
practice. 

In proportion to the reliance placed upon symptomatology in 
the differentiation of typhoid and malarial fevers so frequently 
will mistakes occur. Chills, continued fever, bronchitis, en- 
larged spleen, slight tenderness and gurgling in the right iliac 
fossa, tympanites, diarrhea, the Diazo reaction, delirium, and 
the typhoid state may occur with either disease. Herpes is 
strongly indicative of malaria and rose spots of typhoid fever, 
but these spots are more frequently absent than present in the 
typhoid fever of warm countries. 

A correct diagnosis must rest upon the results of the exami- 
nation of the blood and the therapeutic test. 

The number, either absolute or relative, of the leukocytes 
is not as valuable in this connection as elsewhere, and if the 
case is seen early the diagnosis may be made before the Widal 
reaction is applicable, but this latter test is eminently useful in 
many cases. 

Proper prophylactic precautions should be observed from 
the start in cases of doubtful diagnosis. 

Tuberculosis is sometimes similar in its course to malaria. 
It is especially so in the early stage when the local signs and 
symptoms are ill-defined or absent and the bacillus cannot be 
detected, and in the stage of secondary infection when septic 
symptoms supervene. Miliary tuberculosis has not infrequently 
been mistaken for malaria. For the diagnosis between tuber- 
culosis and malaria the microscopic examination of the blood 
and sputum, the physical examination, and therapeutic test are 
usually ample. 

Influenza has sometimes been confused with malaria. If 
the epidemic occurrence, different seasonal prevalence, catarrhal 
and other symptoms are insufficient upon which to make a 
diagnosis, the absence of characteristic blood findings are gen- 
erally conclusive. 

Yellow fever in some cases so closely resembles the so-called 
bilious remittent fever that in regions where both diseases occur 
the differential diagnosis by clinical history alone is impossible. 



DIAGNOSIS 287 

In such instances the microscope becomes an instrument of the 
greatest good not only to the individual, but to the community. 

The frequency with which dysentery is associated with mala- 
ria as a complication and as a sequel renders the microscopic 
examination of the blood very important in these cases. 

Patients with syphilis manifesting quotidian fever not in- 
frequently receive quinine instead of antisyphilitics. The 
microscope, the therapeutic test, and the history should form 
the basis of the diagnosis. 

Before the geographic distribution of the hookworm and its 
importance in the production of anemia became recognized 
uncinariasis was not distinguished from chronic malaria and 
cachexia. The detection of the ova in the feces and the pres- 
ence of eosinophilia and the absence of parasites and the sub- 
sidiary evidences of malaria in the blood render such a mistake 
at the present time inexcusable. 

Leukemia must occasionally be taken into consideration in 
the differential diagnosis of malaria, in which case the micro- 
scopic examination of the blood is absolutely essential. 

The differentiation of Banti's disease from chronic malaria 
and cachexia may be extremely difficult. We will not solve the 
mysteries of splenomegaly until we learn a safe method of 
obtaining blood from the spleen. 

THE DIAGNOSIS OF PERNICIOUS MALARIA 

It is only since Laveran's revolutionizing discovery that the 
diagnosis of pernicious malaria has been reduced almost to 
exactitude. Cases have already been recited where the parasites 
were scanty or even missed in the blood, but these are only 
rare exceptions. In the immense majority of cases examina- 
tion of the peripheral blood will reveal the presence of the 
organisms. The value of this is inestimable and is paralleled 
only by the importance of making blood examinations in all 
cases. It may be safely said with Craig 70 that hundreds of 
lives have been sacrificed to pernicious malarial fever which 
could have been saved had an examination of the blood been 
made. It is not extremely uncommon in our cities for subjects 



288 THE STUDY OF MALAEIA 

of pernicious attacks found in coma to be taken to the police 
station instead of the hospital and the true condition not sus- 
pected until the patients fail to "sober up" in due time, when 
it is usually too late for treatment to avail. 

Negative examinations of the peripheral blood in desperate 
cases justify risking the dangers of splenic puncture. 

In cases showing the presence of parasites complications 
must be rigidly excluded. In some cases this is attended with 
difficulties. 

In comatose malaria, besides the evidence obtained by an 
examination of the blood, a history of exposure to or attacks 
of malaria, the general appearance and age of the patient, the 
absence of atheroma, the early elevation of temperature, and 
perhaps the enlargement of the spleen and slight jaundice 
should exclude cerebral hemorrhage. The differentiation of 
malarial coma from sunstroke is often hard; in fact, the two 
not infrequently co-exist, in which case it may be impossible 
to apportion the etiologic share of each in the clinic picture. 
Cardamatis 287 states that in this type of pernicious malaria 
coma is the dominating symptom, while in sunstroke are ob- 
served coma, convulsions, delirium, and hyperpyrexia. Uremic 
coma may simulate that due to malaria. Unfortunately, the 
urinalysis throws no light on the diagnosis, as in both condi- 
tions we may find albumin and casts. The blood examination, 
the temperature, and the anamnesis serve to make the diagnosis. 
For the differentiation of alcoholic from malarial coma the 
blood examination is essential. The history may be of value, 
but the odor of the breath may be misleading. To discriminate 
between malarial coma and diabetic coma the presence of the 
parasites, on one hand, and of glycosuria, on the other, are 
sufficient. In differentiating between the various comas with 
reference to malaria two points should be remembered : First, 
that comatose malaria may occur in persons with the odor of 
alcohol on the breath, and, secondly, that coma from causes 
other than malaria may attack malarial cachectics. To distin- 
guish epilepsy, opium poisoning, tetanus, and meningitis from 
pernicious malaria should rarely present difficulties if the blood 
is examined. The following table of different features of 



DIAGNOSIS 289 

amblyopia due to quinine and to malaria is borrowed from 
Manson : 59 

Quinine Amblyopia. Malarial Amblyopia. 

History. — Quinine taken in large History. — Quinine may have been 

doses, not less than 30 grains. taken, but not necessarily in large 

doses. 

Onset. — Sudden, accompanied by Onset. — Not usually sudden, but it 

deafness ; both eyes are affected. may be so if hemorrhage has oc- 
curred in the macular region. 
There is no deafness, and both 
eyes are not necessarily affected. 

Pupils. — Widely dilated, and while Pupils. — React to light, 
loss of vision continues they do 
not react to light. 

Vision. — Completely lost for a time. Vision. — Never completely lost. 

Ophthalmoscopic Appearances. — A Ophthalmoscopic Appearances. — 

white haze over fundus ; cherry- There is optic neuritis ; optic disk 

red spot at macula ; optic disk is of characteristic grayish-red 

pale ; retinal vessels markedly color ; retinal hemorrhages and 

constricted. sometimes vitreous opacities. 

Termination. — Usually some per- Termination. — Some cases recover 

manent defect in the field of completely; in others greater or 

vision or in color vision. Cen- less permanent defect of vision 

tral vision recovers first ; optic remains, 
disk is unusually white, and reti- 
nal vessels small. 

Treatment. — Stop quinine. Amyl- Treatment. — Give quinine, 
nitrite has been recommended to 
induce dilation of retinal vessels. 

Algid attacks sometimes resemble perforation, or typhoid, or 
gastric ulcers, or rupture of the spleen. The microscope and 
the local symptoms should render the diagnosis certain. The 
cases resembling appendicitis and peritonitis have been men- 
tioned; here, again, the microscopic examination of the blood 
may save lives. In countries in which cholera is endemic the 
diagnosis between this disease and the choleraic type of perni- 
cious malaria was formerly difficult or impossible. Laveran's 
discovery has removed this difficulty and rendered possible a 
diagnosis of the utmost importance. The finding of the hema- 
tozoa differentiates the hemorrhagic, bilious, and typhoid types 
from typhoid and yellow fevers. 

DIAGNOSIS OF HEMOGLOBINURIC FEVER 

This is usually made and, as a rule, correctly before the 

physician arrives. The history of malaria, the fever, vomiting, 

jaundice, and black water are pathognomonic. Though the 

parasites are so frequently missed, on examination of the blood 

19 



290 THE STUDY OF MALARIA 

there is usually a mononuclear leukocytosis, and pigmented 
leukocytes may be found. 

The diagnosis from paroxysmal hemoglobinuria might pre- 
vent difficulties. In this rare condition the attacks usually fol- 
low chilling of some portion of the body, and the attack is 
usually of short duration and seldom fatal. In hemoglobinuric 
fever there is given a history of several years of residence in an 
endemic region, repeated attacks of malaria, with often the 
presence of parasites, pigmented leukocytes, and a mononuclear 
leukocytosis in the blood. 

The conditions which have been most frequently confounded 
with hemoglobinuric fever are yellow fever and bilious remit- 
tent fever. 

In localities where yellow fever and blackwater fever prevail 
their differentiation is not easy. The following are the chief 
points of difference : 

Hemoglobinuric Fever. Yellow Fever. 

Endemic. Epidemic. 

One attack predisposes. One attack confers immunity. 

Occurs usually after several years Attacks also new comers. 
of residence. 

Malarial history always given. May be no history of malaria. 

Prodromata common. Uncommon. 

Icterus intense, early, always pres- Icterus usually slight, begins on 
ent. third or fourth day; may be ab- 

sent. 

Conjunctiva jaundiced. Usually congested at first. 

Hemoglobinuria. Albuminuria or hematuria. 

Blood may show malarial parasites, Absent, 
pigmented leukocytes, and mono- 
nuclear leukocytosis. 

Bilious vomiting. Vomit clear or black. 

Hemorrhages uncommon. Relatively common. 

Spleen usually much enlarged. Enlargement slight. 

Increasing pulse. Pulse retards with stationary or in- 

creasing temperature (Faget's 
sign). 

Albuminuria from beginning. Usually appears from second to 

fourth day. 

A rather striking coincidence is the relative immunity of the 
negro to both diseases. 

Certain cases of bilious remittent fever present points of 
striking similarity. This is well illustrated by the following 
case which was represented to me by the messenger and by 
the family on my arrival as one of "hematuria" : 



DIAGNOSIS 29I 

A. H., white, male, aged thirty-nine, timberman, lived in a 
malarial country eighteen years. Never had hemoglobinuria 
fever. He had been having chills at intervals all summer and 
fall, slight fever, "dumb chills," and slight jaundice for three 
weeks ; no quinine for two months ; badly salivated from seven 
large doses of calomel taken several days ago. Examination 
November 29, 1906, four and a half hours after first passage 
of "bloody water." Temperature, 99*/ 5 ; pulse, 92 ; marked 
jaundice of skin and sclera; has been vomiting; liver region 
tender ; spleen extends to anterior superior spinous process and 
to within i J / 2 inches of the umbilicus. Blood examination 
showed two large pigmented, intracorpuscular parasites, hemo- 
globin 65 per cent. Urine "port wine" color, acid 1.014; nitric 
acid test for albumin negative, biliary coloring matter abun- 
dant, no hemoglobin. Microscopic examination negative. Un- 
der quinine treatment the urine cleared in thirty-six hours and 
the fever left in a few days, going no higher than 101 1 / 2 . The 
anemia and enlarged spleen were yet present when I last 
saw the patient, two weeks after the attack. 

The following scheme will help to differentiate hemoglobin- 
uric fever and bilious remittent fever : 

Hemoglobinuria Fever. Bilious Remittent Fever. 

Onset sudden. Onset slower. 

Jaundice develops rapidly and be- Jaundice develops more slowly and 

comes intense. is not so intense. 

Parasites frequently absent. Parasites usually present. 

Albuminuria constant. Albuminuria not constant. 

Urine colored by hemoglobin or its Urine colored by bile. 

derivatives. 

The differential diagnosis, as attempted by some writers, 
from "quinine poisoning in malarial subjects" is futile and im- 
possible, as this condition is a mode of hemoglobinuric fever. 



CHAPTER VII 



PROGNOSIS 



Spontaneous Recovery. — It is a familiar fact that malaria, 
after the manner of other infectious diseases, not infrequently 
undergoes what is termed spontaneous cure. Physicians in 
malarial regions often see patients whose paroxysms, typic and 
with characteristic periodicity, have ceased without medication 
or after nothing but a purgative dose. 

It is doubtful, however, whether this cessation may with pro- 
priety be termed a cure. In the majority of instances relapses 
follow at shorter or longer intervals. It is better, therefore, 
for practical purposes to consider this but a transition from 
active malaria to latency. The greater frequency with which 
gametes are found after the so-called spontaneous recovery 
justifies this assumption. 

Spontaneous cure occurs more frequently in tertian and 
quartan infections. This statement applies merely to the tem- 
porary cessation of paroxysms and not to the tendency to re- 
lapse. 

It is more frequently observed in the negro than in the white 
race, permanent cures occurring not rarely in the former race 
in the absence of all medication. 

Sex may exert a slight influence upon the tendency to spon- 
taneous recovery, the female, on account of less severe exposure 
to deleterious influences, probably manifesting a greater dis- 
position. 

The discontinuance of paroxysms may be sudden or more 
often gradual, the accesses becoming less severe or the interval 
longer, or in infections with more than one generation of para- 
sites one may be suddenly destroyed, the others later. 

Prognosis. — This is influenced to some extent by locality. 
It is manifest that in regions where only the tertian and quartan 

292 



PROGNOSIS 293 

infections are prevalent the mortality is less than where severe 
estivo-autumnal fevers are widespread. There is, furthermore, 
quite a difference in the mortality rate in countries where the 
estivo-autumnal infections are equally distributed. 

Race as a factor in the mortality of malaria has already been 
dealt with. 

A majority of deaths from malaria occur in children. There 
is no doubt but that many children die of malaria which has 
not been diagnosed in time. In the young pernicious symptoms, 
especially cerebral, are prone to supervene, or the attack may 
be followed by extreme anemia and dropsies. Malaria is like- 
wise much more serious in advanced age than in the interme- 
diate ages. 

Occupation and social conditions play a part in prognosis. 
Excessive toil and exposure may render pernicious attacks 
otherwise benign, and timely treatment, usually resorted to by 
the better classes, enhances the chance of recovery. 

The outlook is probably more favorable in attacks occurring 
without the malarial season than within. 

Manifestly the condition of the patient with reference to the 
results of previous disease is of importance. Anemia, alcohol- 
ism, dysentery, and other conditions not fully recovered from 
contribute gravity to the prospect. 

The type of malarial infection is of the greatest importance. 
In the tertian and quartan types it is only very rarely that 
serious symptoms result. It is not yet certainly known in 
which variety of estivo-autumnal infection the prognosis is 
most grave. While Marchiafava and Bignami 162 and Manna- 
berg 141 hold that the tertian estivo-autumnal infections are 
most often attended with danger, Craig 70 and Wright 38 main- 
tain the opposite view. 

Postponement and anticipation of the paroxysms were for- 
merly regarded as favorable and unfavorable, respectively. 
However, owing to the irregularity of the estivo-autumnal 
fevers, these can be said strictly to be properties of tertian 
and quartan infections only, and are consequently of little prog- 
nostic import. Violent headache, somnolence, sighing respira- 
tion, slight mental aberration, defective articulation and vision, 



294 THE STUDY OF MALARIA 

cold surface, and rapid, feeble purse are some of the symptoms 
which forebode evil. 

The prognostic value of the microscopic examination of 
the blood is limited. While, as a general rule, the severity of 
the attack is in proportion to the number of parasites, these 
are sometimes scanty in the peripheral circulation even in grave 
cases. Sporulating and advanced stages of estivo-autumnal 
parasites are rarely seen in the superficial blood except in 
extremely severe cases. 

Delaney 346 regards a reduction of leukocytes to or below 
1,500 as of grave prognostic value. The writer is unable to 
verify this from his experience, since in his cases of pernicious 
malaria there has existed a leukocytosis. 

While in tertian and quartan infections a paroxysm may be 
predicted approximately from the results of blood examination, 
such an attempt with estivo-autumnal malaria may prove mis- 
leading. An impending paroxysm dependent on mature para- 
sites in the visceral circulation cannot be foretold. 

Intercurrent diseases complicating malaria aggravate the 
prognosis. This is especially the case in chronic malaria and 
cachexia, with which pneumonia, dysentery, and other diseases 
form frequently fatal associations. 

The gravity of pregnancy as a complication of malaria has 
been considered. 

In nephritis of malarial origin the prospect is, as a rule, 
good. If, however, the patient is repeatedly subjected to 
malaria or other harmful influences the prognosis is not propi- 
tious. 

The prognosis of the nervous sequelae is ordinarily favor- 
able. The various paralyses and mental symptoms are gener- 
ally transitory, but may occasionally become persistent. Bulbar 
symptoms are usually slow to disappear. 

The course of chronic cachexia may be extended for years ; 
acute cachexia runs a more rapid course. In mild cases a 
change of climate and tonic treatment do a great deal for the 
patient ; advanced cases rarely recover. Death may occur 
from exhaustion, but is more commonly due to pernicious 
malaria and to complications, of which the most frequent are 



PROGNOSIS 295 

pneumonia and nephritis. Hence the danger to the cachectic is 
not confined to the malarial season, but he is in danger through- 
out the entire year. 

Mortality. — The true mortality of malaria is difficult to 
estimate. While statistics are not lacking, the different condi- 
tions under which they are compiled must be considered, some 
being from charity hospitals, some from private practice, some 
from military practice, from various localities, etc. It is, fur- 
thermore, undoubtedly true that a considerable proportion of 
malarial cases does not come to the notice of physicians. The 
variety of forms which malaria assumes is another obstacle. 
It is probable that many cases ascribed to complications, fan- 
cied or real, are due to malaria. 

Bearing these points in mind, the following figures are pre- 
sented, showing a mortality of 2.89 per cent. : 

Author. Locality. Cases. Deaths. 

Laveran 1 Turko-Russian War. . 140,000 1,092 

Laveran 1 Constantine 1,310 

Laveran 1 Italian Army 4,856 13 

Schellong 8 " New Guinea i,9S4 22 

Ross 3 * 8 Greece 960,048 5,916 

Ross 349 Hong Kong 7,352 984 

Ewing 27 Camp Wikoff 605 39 

Smart 78 Civil War 1,373,355 15,423 

Travers 38 Malay States 3,397 348 

Terburgh 84 Dutch Indies 2,308,128 114,490 

Cardamatis 68 Athens 22,618 15 

Koch 34 Grosseto 281 

Koch 172 East Africa 63 2 

Hagen 350 Papua 301 23 

British Colonial Reports 351 British Colonies 12,617 618 

Wright 38 British Malaya 17,468 680 

Haw 352 Baberton 449 14 

Hope 40 North Bengal 1,784 

Laveran 353 Algiers 98,774 7,432 

Gorgas 354 Panama 1,055 5 

Erni 81 Dutch Indies 116,879 73* 

United States Marine Hospital 355 . .General 6,618 20 

Various Hospital Reports Southern States 1,294 3° 

German Protectorate Reports 356 . . .German Protectorates 5,003 32 

Malaria Society 37 Italy 22,792 120 

5,109,001 148,055 

Prognosis of Pernicious Malaria. — The prognosis of per- 
nicious malaria is extremely grave. It depends upon the physic 
condition and age of the patient, the type and severity of the 
attack, and the promptness and efficiency of the treatment. 



296 THE STUDY OF MALARIA 

Anemia from previous attacks of malaria or other causes, 
alcoholism, or organic disease of important viscera acid to the 
gravity of the case. The cerebral types are less serious in the 
young and vigorous, very fatal in the aged. As a rule, patients 
seen early and treated skilfully and energetically have a better 
chance for life, but many cases end fatally in spite of the best 
and most timely treatment. 

The number of parasites in the peripheral circulation is not 
always a reliable guide as to the severity or progress of the 
attack. With apparent amelioration of the symptoms the 
physician should be circumspect in his prognosis and bear in 
mind the possibility of further paroxysms. 

In the writer's opinion, the algid type is the most lethal, 
the typhoid and the dysenteric least so, though this is not 
exactly in accord with Colin, 291 who arranges the types accord- 
ing to the following descending scale of gravity : Syncopal, 
algid, cardialgic, delirious, comatose, icteric, choleraic. Schel- 
long 92 regards the comatose as the most dangerous, and Le 
Dantec, 26 the delirious and algid. 

Parry 357 states that average mortality of pernicious malaria 
is 1 out of every 8 cases ; Wharton 358 estimates it as 1 of every 
12 or 15; Haspel 86 and Borius, 149 one-third; Pampoukis, 86 
21.4-25.4 per cent.; Le Dantec, 226 20-50 per cent, and Cres- 
pin, 144 20-70 per cent. The algid type is said by Pampoukis 86 to 
be fatal in 55.5 per cent, of cases. Cardamatis 287 states that 
the comatose variety is fatal in 20-40 per cent. ; Bergeand 359 
believes the mortality of this type to be 50 per cent. 

The following list of 27,039 cases of pernicious malaria, 
compiled from the literature, shows a mortality of 26.6 per 
cent. The first column of figures shows the number of cases, 
the second the number of fatalities : 

Number of Number of 
Cases. Deaths. 

Laveran 1 104 53 

Bailly 360 886 341 

Nepple 8 " 14 6 

Antonini and Monard 66 39 9 

Maillot 88 186 38 

Grail 256 117 75 

Burot and Legrand 212 210 142 

Smart 76 16,209 4,164 

Travers 38 260 81 



PROGNOSIS 297 

Number of Number of 
Cases. Deaths. 

Martirano 15 ' 19 9 

Pezza 8< 2 1 

Tanzarella 81 31 8 

Thayer and Hewetson 29 3 2 

Plehn 6 10 1 

Maillot 362 7 6 

Theophanidis 362 5 2 

Cardamatis 363 3 2 

Pampoukis 363 52 2© 

Billet 1 " 40 2 

Segard 79 24 15 

MaureP 156 77 

Caccini 147 135 56 

Martirano" 7 6 3 

Charity Hospital, New Orleans 361 8 6 

Neer 156 3 3 

Celli 83 8,032 1,879 

Cardamatis 68 50 9 

Colonial Reports 351 252 133 

Kelsch and Kiener 178 89 51 

Albini 82 87 11 

27,039 7,205 

Six hundred and eighty-nine cases of specified type give 
the following respective mortalities : 

Comatose. Delirious. Algid. Typhoid. Ataxic. 

Maillot 86 77-14 61-12 48-12 

Schellong 62 7-6 

Plehn 5 10-1 

Maillot 362 .... 7-6 

Theophanidis 362 5-2 

Cardamatis 363 3-2 

Pampoukis 267 52-20 

Billet 151 .... .... 40-2 

Maurel 75 279-103 78-23 22-17 

Neer 156 3-3 

Total 428-147 61-12 141-45 40-2 22-17 

34% 20% 32% s% 77% 



The Prognosis of Hemoglobinuric Fever. — The prognosis 
of hemoglobinuric fever is grave, and should be "guarded and 
Delphic." Probably the most valuable prognostic sign is the 
quantity of urine ; the chemic analysis and microscopic exami- 
nation are not of great value in prognosis. Anuria, the most 
dreaded symptom, is to be feared if the daily quantity of urine 
falls below 200 cc. If suppression supervenes the outlook is 
extremely serious and is unfavorable in proportion to early 
onset. When a patient is tided over a period of suppression, 



298 THE STUDY OF MALARIA 

as occasionally happens, he usually dies during convalescence 
of exhaustion, subsequent nephritis, or embolism. 

Excessive and uncontrollable vomiting is a bad omen, ex- 
hausting the sufferer and interfering with nutrition and medi- 
cation. Diarrhea is probably in many cases, with suppression 
or a tendency thereto, a life-saving measure, and may be par- 
tially responsible for the relative rarity of uremic symptoms 
under these circumstances. Singultus is present in a majority 
of fatal cases, and when obstinate is always unfavorable. Re- 
mittent or intermittent temperature is usually favorable. Som- 
nolence, with diminishing amount of urine ; coma, especially of 
early onset, petechise, epistaxis or other hemorrhage, and algor 
forebode evil. 

Thrombus formation in the heart or large vessels may cause 
sudden death when the patient is thought to be progressing 
favorably. Plehn 5 believes that loud heart murmurs accom- 
panied with weak, irregular pulse denote heart thrombus. This 
condition is almost certainly fatal, usually in five to eight days. 

The larger the share partaken by quinine in the etiology of 
the individual case the better the prognosis, provided the case 
is not further aggravated by quinine. 

Cases occurring in victims of malarial cachexia or of com- 
plications are usually more serious. 

The mortality varies unaccountably from year to year, some 
seasons evincing a series of mild cases, others an appalling 
mortality. In a certain parish of Louisiana in 1867 many 
cases are said to have occurred, of which not less than 95 per 
cent, died. 366 Fisch, 191 who placed the mortality on the Gold 
Coast at 20 per cent., states that until two or three decades 
previously nearly all who were attacked died. On the other 
hand, Banks 210 makes the well-nigh incredible statement that 
he treated over 100 cases in the Congo State without a death. 

Pampoukis 96 gives the mortality of blackwater fever as 
6.6 per cent. ; Crosse, 4 20 per cent. ; Kanellis, 867 22.4 per cent. ; 
Berenger-Feraud, 96 23.1 per cent.; Barthelemy-Benoit, 96 25 
per cent. ; Bertrand, 229 25 per cent. ; Carre, 191 27 per cent. ; Cas- 
san, 98 32.1 per cent. ; Michel, 868 33 to 50 per cent. ; Schellong, 191 
42 per cent. ; Reynolds, 367 50 per cent. ; Scott, 367 60 per cent. 



PROGNOSIS 299 

The following list of 6,037 cases, with 1,268 deaths, shows 
a mortality of 2 1 per cent. It is compiled from various sources. 

The first column of figures shows the number of cases, the 
second the number of deaths : 

TREATED WITH QUININE, 1821 CASES, 472 DEATHS, 25.9% 

Number of Number of 

Cases. Deaths. 

Vieth 8 14 3 

Dryepondt 8 28 1 

Mense 234 22 

Powell 234 9 7 

Gelpe 2 " 3 2 

Diesing 234 2 2 

Hagge 234 7 2 

Schellong 234 7 3 

Reynolds 234 1 1 

Doering 1 " 6 

Hanley 184 13 3 

Moffatt 263 9 2 

Gorgas 354 20 3 

SteudeP 18 3 

Malone 369 120 14 

Brem 215 14 2 

Coste 370 IS 7 

Steggall 371 3 

Woldert 240 5 

Otto 63 1 

Schlayer 222 1 

Austin 372 1 

Herrick 251 8 

Curry 186 1 1 

Burot and Legrand 225 3 1 

Cardamatis 206 1,352 354 

Broden 242 12 7 

Theophanidis" 3 23 14 

Oeconomou 373 18 5 

McDanieF 4 85 35 

TREATED WITHOUT QUININE, 1006 CASES, 112 DEATHS, 11.1% 

Number of Number of 

Cases. Deaths. 

Tomaselli 232 30 6 

Navarre 8 2 

Henric 375 2 

Kohlstock 376 48 8 

Koch 172 16 3 

Hopkins 260 6 1 

Bertrand 229 21 2 

Ollwig 49 IS 

Wittrock 49 4 1 

Ziemann 49 12 4 

A. Plehn 191 53 5 

Kleine 223 15 1 

Krauss 199 15 

McElroy 214 25 4 

Goltman and Krauss 189 . 12 9 



3°° 



THE STUDY OF MALARIA 



TREATED WITHOUT QUININE, 1006 CASES, 112 DEATHS, 11.1% 



Number of 
Cases. 

Malone 369 35 

Coste 870 10 

Hearsey 260 15 

Seal 268 6 

Ruge 239 

Dryepondt and Vancampenhout 228 

Howard 216 

Ketchen 238 

Masterman 64 

Herrick 2 " 

Curry 188 

Cardamatis 206 456 

Ensor 377 11 

Broden 242 25 

Pancot 243 7 

Theophanidis 3 " 9 

Oeconomou 373 31 

McDaniel 374 93 

F. Plehn 5 25 



Number of 
Deaths. 



I 
I 

I 

33 
I 
2 
I 

2 
16 

I 



TREATMENT MIXED OR NOT RECORDED, 3210 CASES, 684 

DEATHS, 21.3% 

Number of Number of 

Cases. Deaths. 

Kanellis 232 20 4 

Poole 8 56 15 

Rothschuh 8 20 18 

Guiol" 8 185 49 

Gouzien 379 53 

Meixner 40 40 6 

Hofft" 14 6 

Wendland 49 10 

Daniels 57 184 41 

Wellman 68 34 S 

Ipscher 90 20 1 

Krueger 90 11 2 

Simon 99 17 3 

Kerr Cross 380 27 9 

Osborn 14 10 5 

Berenger-Feraud 98 286 66 

O'Neill 98 50 2 

Burns 235 16 6 

Shropshire 287 177 35 

Dempwolff 381 17 2 

Lipari 202 19 5 

Gouducheau 246 15 4 

Cochran 382 642 158 

Kelsch and Kiener 178 109 35 

Bolton 383 175 38 

GralP 6 113 13 

Forde 384 2 1 

Grenet 373 68 8 

Rousseau 373 22 6 

Carmouze 373 30 9 

Mericourt 373 22 3 

Koryllos 373 28 5 

Pampoukis 373 156 35 



PROGNOSIS 301 

TREATMENT MIXED OR NOT RECORDED, 3210 CASES, 684 

DEATHS, 21.3% 

Number of Number of 
Cases. Deaths. 

Cardamatis 3 " 30 6 

Parathyris 373 23 3 

Prout 386 24 8 

Jacobs 387 147 16 

DeCruz 388 13 6 

DeBlasi 389 3 

Orme m 2 

Thompstone 381 27 5 

German Protectorate Reports 350 293 45 

Total 6,037 1,268 

F. Plehn 5 asserts that mortality is highest in first attacks, 
but the following table of Daniels 57 does not bear him out : 

Of 136 first attacks 31 or 22.7 per cent, were fatal 

Of 33 second attacks 8 or 24.0 per cent, were fatal 

Of 15 third or fourth attacks. 2 or 13.3 per cent, were fatal 



CHAPTER VIII 

PROPHYLAXIS 

The immortal discovery of Ross is to the prophylaxis of 
malaria what that of Laveran is to the diagnosis, and, although 
recent, has already been instrumental in saving untold suffer- 
ing, incalculable economic loss, and thousands of human lives. 

It has been explained how the parasite is abstracted by cer- 
tain species of mosquitoes with the blood of infected indi- 
viduals, undergoes essential changes in the body of the mos- 
quito, and is then inoculated into healthy persons. It is, there- 
fore, evident that if this cycle be broken at any point infection 
cannot occur, and that if it were universally interrupted during 
a sufficiently long period of time the disease would be annihi- 
lated. Hence prophylactic measures may be directed against 
the destruction of the malarial parasites within the body of 
man, the destruction of the mosquitoes which are capable of 
transmitting the parasites, and the prevention of mosquitoes 
gaining access to man. The parasite may be opposed either in 
man or in the mosquito. The mosquito may be combated 
either in its aquatic or in its aerial stage. Prophylaxis may 
be conducted by a community or by an individual, may be 
public or private, offensive or defensive. 

As is well known, malaria is now almost or entirely absent 
from regions in which it was formerly very prevalent, and in 
other places is rapidly diminishing. In the regions in mind the 
change was independent of designed efforts for the eradication 
of the disease ; in fact, it occurred in most instances before the 
discovery of either the malarial parasite or of the role of the 
mosquito in the dissemination of the disease, and was an un- 
expected result of the progress of civilization. This uncon- 
scious prophylaxis was probably the product of several factors, 
which may be classed as agricultural, therapeutic, and hygienic. 

302 



PROPHYLAXIS 303 

I. Lowering of the ground water and consequent diminution 
of breeding pools through drainage for reclamation of swamp 
lands, clearing and cultivating of lands, construction of levees, 
etc. 2. More radical cures of malaria by means of cinchona 
bark and its derivatives, lessening the number of cases of 
latent malaria, thereby diminishing the sources from which 
parasites might be obtained. 3. Improved hygienic conditions, 
better homes and food, the installation of water and sewerage 
systems, improved road and street grading, the use of screens, 
mosquito bars, etc. For very few other diseases has uncon- 
scious prophylaxis done so much as for malaria. This is still 
exemplified in regions where malaria is yet endemic; those 
who live under the best hygienic conditions suffer least from 
malaria, though they may even be ignorant of the manner of 
its propagation. 

With the tediously attained and in many cases incomplete 
results of this unconscious prophylaxis are in decided contrast 
the consequences of well organized and vigorous sanitary 
measures directed toward the prevention of malaria. Many 
instances could be adduced where within a comparatively short 
space of time highly malarial localities have been almost com- 
pletely freed from the disease, but a few examples will suffice. 

One of the most successful campaigns against malaria was 
that at Ismailia, a town of about 8,000 inhabitants, near the 
middle point of the Suez Canal. The town was founded in 
1862, and was celebrated for its salubrity until 1877, when 
malaria was introduced and spread rapidly; in 1886 nearly 
all the inhabitants were attacked. In 1901 the president of 
the Suez Canal Company, learning something of the results 
of modern prophylactic methods, dispatched Pressat, a member 
of the medical staff, to Italy to study the subject, and invited 
Ross to inspect the place and advise upon the most suitable 
manner of conducting the campaign. In September, 1902, 
Ross arrived in company with MacGregor and with Pressat 
returning from Italy. An abundance of anophelines were 
found in the houses of the employes, and the larvse, especially 
in small, brackish marshes, in the sand, and in some of the 
waters of irrigation, but not in the main canal, where they 



304 THE STUDY OF MALARIA 

were probably destroyed by fish. It was evident that mosquito 
reduction was to be the chief end, though old cases of malaria 
received vigorous treatment. Marshes were filled with sand 
and the irrigation channels were deepened or treated with oil. 
This preliminary work was conducted with a brigade of only 
four men, though many others were employed later for the 
extensive permanent work. From 1885 until 1902 inclusive 
the number of cases of malaria at Ismailia had averaged nearly 
1800 annually. In 1903 there occurred 214 cases; in 1904, 
90, and in 1905 only 37. It is said that it is now possible to 
sleep with comfort in the place without nets. The cost of the 
campaign is estimated at an initial expenditure of 6.25 francs, 
and an annual outlay of 2.3 francs per head of population. 

The results of the campaign conducted by Travers and Wat- 
son at Klang and Port Swettenham, in the Federated Malay 
States, are hardly less striking. Klang had 3,576 inhabitants 
in 1 901. Port Swettenham, five miles away, had a population 
of about 700. The population of the district surrounding the 
two towns was about 14,000. In the latter part of 1901 
malaria was so extensively prevalent that probably not more 
than three houses in Klang escaped infection, and Port Swet- 
tenham was being abandoned by the workmen. . The antimala- 
rial campaign, which was confined to the towns of Klang and 
Port Swettenham, began in 1902. Swamps were filled, a con- 
tour drain established to intercept incoming water from sur- 
rounding springs, and forest and mangrove trees were felled. 
After the epidemic had begun to subside screens were furnished 
many of the houses and quinine was distributed. The cost of 
the operations to the end of 1905 consisted of a primary 
expense of £10,100 and an annual expense of £410. 

The following table shows the mortality from malaria within 
the towns as compared with that of the unprotected district : 

1900 1901 1902 1903 1904 1905 

Towns 259 368 59 46 48 45 

District 173 266 227 230 286 351 

The most brilliant results in the prophylaxis of malaria were 
those obtained by Gorgas in Panama, one of the most insalu- 
brious regions upon the face of the earth, having been called 




Fig. 75. — The barrels and one of the buckets contained many larvae. 




Fig. 76. — Anopheles larvae in the barrel. A fatal case of comatose malaria 
occurred here a few weeks before the picture was taken. 




Fig. 77. — Unmindful of the danger lurking in the barrel. 




Fig. 78. — Fire barrels containing larva;. 




Fig. 79. — Water barrels may prevent the spread of fire, but will breed mos- 
quitoes unless covered. 




Fig. 80. — Stock pond containing anopheles larvae. Too near the dwelling. 




Fig. 81. — A protected pool in a lumber-yard containing myriads of anopheles 

larvas. 




Fig. 82. — A typical " bayou," the headquarters of malaria. 




Fig. 83. — An ill-chosen town site along the bayou. 



PROPHYLAXIS 305 

during French occupation "the Frenchman's Grace." It is a 
common report that in the railroad between Panama and Colon 
every cross-tie represents the corpse of a laborer. 

The canal zone is fifty miles in length, with Panama and 
Colon at each end. The average number of employes is 40,000. 
The efforts consisted in the destruction of breeding places only 
within 200 yards of the camps and villages, no attempts being 
made to deal with those farther off. All the houses were 
screened and the people were urged to use mosquito bars. 
Quinine was furnished them and they were advised to take 3 
grains daily. The abolition of the breeding pools was regarded 
as a most important measure. Owing to the heavy rainfall and 
the luxuriant vegetation the ditches filled rapidly with grass, 
and it was found much cheaper to concrete them. Subsoiling 
by means of the tile drain covered with rock and soil was used 
wherever possible. 

The result is that the death rate has been lowered until it 
does not exceed that of New York City. 

I. MEASURES DIRECTED FOR THE DESTRUCTION OF 
MOSQUITOES 

Destruction of breeding pools for the anopheles is an effi- 
cient preventive measure. It is chiefly through the eradication 
of breeding places that so-called unconscious prophylaxis has 
accomplished its results. This method has received the chief 
consideration in the greatest antimalarial campaigns. It is 
more permanent and possesses the further advantage in many 
instances of being cheaper in the end. 

It is neither necessary nor in every case advisable to remove 
the surface water from the whole of a malarial country, but 
only in the region of habitations or where anopheles are known 
to breed. In the Panama campaign the area of destruction 
extended only 200 yards from camps and habitations. This 
should probably be the minimum radius, though work at a 
much greater distance is only a useless expense. 

In the area to be protected the land should be cleared of 
weeds, undergrowth, bushes, and unnecessary trees to pro- 
mote evaporation and prevent the formation of puddles. 
20 



306 THE STUDY OF MALARIA 

Grocery cans, broken bottles, buckets, and old tinware which 
might retain water should best be buried. Water-barrels, tanks, 
cisterns, and wells should be emptied, filled, or screened. Gut- 
ters should be maintained in such a condition that water cannot 
accumulate. 

The stock pond, so common in the vicinity of habitations in 
some sections, is a menace to both man and beast and should 
not be tolerated. 

The care of streams and large bodies of water is ordinarily 
simple, since these rarely threaten sanitation as anopheles 
breeders. Within the protected area the banks should be 
cleared of dense weeds and bushes, eddies prevented where 
possible, and pools along the edges drained into the channel. 

In the case of streams that get very low after the rainy 
season, leaving a chain of pools along the river-bed, these pools 
should be drained into each other and an attempt made to 
reestablish a flow and to permit of scouring and the access of 
fish from the larger pools. Where the pools are small much 
water can be gotten rid of by the use of brooms. 

In the case of large bodies of water subject to overflow the 
problem is more difficult. The primary effect of the submerg- 
ing of land, while the water is high, is to diminish malaria. 
The secondary effect, after the waters have receded, is to 
cause a marked increase. A remarkable example which illus- 
trates this occurred in Holland in 1748. The Dutch allowed 
the land, for defensive purposes, to become overflowed. Peace 
being concluded during the middle of the summer, the inunda- 
tion was caused to subside, whereupon a serious outbreak of 
malaria occurred. The epidemic was not successfully com- 
bated until the land was again submerged and kept so until 
the advent of winter. The effect upon malaria of inundations 
is almost yearly observed in the valleys of the Nile, of the 
Mississippi, and of other large streams. Levees, dykes, and 
other engineering" means of large dimensions are the only 
remedies; these being expensive are rarely employed merely 
for sanitary purposes. 

Marshes and swamps when too extensive to be filled may 
be effectively drained. The drains should be narrow, of suffi- 




Fig. 84. — Anopheles breed among the cypress knees. 




Fig. 85. — Many breeding-places are left upon the lowlands after the overflow 

has receded. 




Fig. 86. — A stranded skiff containing a little water and many anopheles 

wrigglers. 




Fig. 87. — The cyclone as a factor in malaria. 




Fig 88. — This pool, fed from the ice-plant, contained larvae weeks after most 
other pools had disappeared. 




Fig. 89. — Hunting for anopheles larvae along the leve'e. 




Fig. 90. — An embryc scientist searching for anopheles larvae. 




Fig. 91. — Breeding pools in the borrow pits along a railroad. 




Fig. 92. — Breeding pools along the roadside. 



PROPHYLAXIS 307 

cient depth and fall to drain effectively, and may be parallel, 
crowfoot fashion or otherwise, as best suited to local condi- 
tions. If concreted they require less after-treatment and may 
be cheaper in the end. If not concreted they should be fre- 
quently inspected to prevent caving, deposit, or filling - with 
vegetation. Tile-drains are usually very efficient. 

Large swamps in the vicinity of streams have been rendered 
unfit as breeding places by directing the course of the stream 
through them. The water is thus given a current, and if the 
stream contains much mud in suspension the bed of the marsh 
is gradually filled. 

Fresh-water ponds close to the sea have been successfully 
treated by filling with salt water. It is said that a large fresh- 
water lake back of the hotels at Virginia Beach which bred 
numerous mosquitoes was filled with salt water by means of 
machinery with a satisfactory result. Water strong in salt is 
not attractive for breeding purposes, though brackish water 
may harbor numerous larvae. 

The rendering innocuous of borrow pits along railroad lines 
(Fig. 91) is difficult. It is much easier to prevent the stagna- 
tion of water during the construction of the road than it is 
to remedy the defect after completion. Filling and drainage 
are the best correctives. It should be the duty of some one 
to see that the construction of railroads, canals, and similar 
enterprises does not render a country more unsanitary. 

The destruction of smaller pools and puddles is usually 
simple and goes far toward prophylaxis, since it is in such 
places that anopheline mosquitoes breed by preference. Filling 
is by far the most permanent, hence the cheapest and most 
desirable method by which to deal with these collections of 
water. Pools in ditches along the sides of roads (Fig. 92), 
wheel ruts, hoofprints of stock in soft ground, water remain- 
ing in natural inequalities in the ground and in excavations 
for various purposes should be assiduously attended. The 
work should be conducted by one who is familiar with the 
rudimentary principles of drainage. The organization for this 
purpose of "mosquito brigades" was first suggested and put 
into practice by Ross, 392 whose advice is as follows : "Attack 



308 THE STUDY OF MALARIA 

first those collections of water the obliteration of which will 
remove the largest number of mosquitoes for the least amount 
of money. Thus it is quite useless to drain stagnant water 
simply because it is stagnant water. The superintendent should 
first assure himself that it does actually contain larvae, and, 
better, that it constantly contains them. As already mentioned, 
some pools are too large, others are too small, and others are 
subject to scouring, and, though these conditions often change 
at certain seasons, when, for instance, large pools dry up, yet 
some pools appear to be habitually unsuited to the larvae. It 
is useless to spend much money over these. Again, it is not 
advisable to attack without discrimination even the pools which 
do contain larvae. Some contain many more larvae than others 
do; and, in my experience, while larvae do occur in some con- 
siderable bodies of water, such as marshes or ponds, they are 
generally much more numerous in small pools. Now, it is 
evidently bad economy to spend large sums over draining large 
bodies of water when small puddles, easily dealt with, really 
cause more mischief. The superintendent must suppose noth- 
ing — he must never suppose because a marsh exists in a neigh- 
borhood that it is the only or the principal cause of malaria. 
He must study the point by careful search for anopheles 
larvae ; and may often find that a small, unobserved pool in the 
street is more dangerous than a marsh a mile away. 

The number and nature of the breeding pools depend so 
much upon the configuration of the ground, the character of 
the soil, and the amount of the rainfall that it is impossible to 
give very minute directions regarding the method of dealing 
with them. The superintendent must be guided by his own 
judgment, remembering only the maxim, which applies to most 
kinds of work, "The simplest measures first." 

The height of the ground water is very intimately associated 
with the prevalence of malaria, since the quantity of surface 
water depends largely upon the height of the ground water, and 
the latter, when appearing upon the surface, is a favorite 
breeding site for malarial mosquitoes. Hence, measures 
directed toward the lowering of the ground water are of the 
highest efficacy in the prophylaxis of malaria. This is evi- 




Fig. 93. — Breeding pools on a rice farm. 



PROPHYLAXIS 309 

denced by the results of the "tiling" of land and by the forma- 
tion of drainage districts for the reclamation of swamp lands. 
Such procedures often render unnecessary the expenditure of 
labor or money for the removal of breeding pools or other anti- 
larval steps. 

Ground water is lowered by various methods, the most 
primitive of which is ditching. These ditches are left open 
or are partly filled with gravel or stone, then with earth. The 
unglazed tile drain is very effective; perforated drains have 
been employed also. 

In certain regions where the hardpan or impervious stratum 
is responsible for a high-ground water excellent results have 
been obtained by boring through this, thereby allowing the 
water to escape into the permeable earth beneath. These are 
the so-called absorbing wells. 

It is well known that rice culture increases the malaria of a 
region to a great extent (Fig. 93). In some of the Oriental 
countries the crop is a necessity, but in regions not absolutely 
dependent upon the crop the cultivation of rice must be looked 
upon as an evil. In fact, some governments have either thrown 
certain restrictions around the industry or have altogether 
prohibited it. 

Since the time of Pliny it has been the theory that trees 
render a locality more salubrious by filtering out miasmatic 
exhalations. The eucalyptus globulus has attained considerable 
reputation in this respect, probably from a belief that it absorbs 
moisture from the soil and renders it drier. Recent experi- 
ments in Italy have, however, shown that this tree has no 
effect in decreasing malaria, and that it even affords an excel- 
lent shelter for anopheles mosquitoes. 

Sunflowers and castor-oil plants, which are reputed to be 
beneficial in the prophylaxis of malaria, are probably devoid of 
such virtue. 

There are circumstances under which it is impossible to 
destroy the breeding pools. Here the use of petroleum is indi- 
cated. This oil is also useful in antimalarial campaigns as 
a temporary measure in part of the work while permanent 
means are being employed elsewhere. 



310 THE STUDY OF MALARIA 

While the value of petroleum as a larvicide was known early 
in the nineteenth century, to Howard belongs the credit of its 
practical application. 

An oil should be chosen which spreads rapidly and evapo- 
rates slowly. The refined illuminating oil evaporates readily, 
hence is too expensive for work on a large scale. The most 
suitable is the fuel oil or blast-furnace oil. The oil, forming 
a film upon the entire surface of the water, chokes the air 
tubes of the larvae, which come to the surface to breathe. 
The pupae expire even earlier than the larvae, since they require 
more air. Furthermore, not a few adult female mosquitoes in 
the act of oviposition are thereby destroyed. . 

The pool should be cleared, as far as possible, from weeds 
and algae which interfere with the spread of the oil. The oil 
should be poured from a watering pot, sprayed by means of a 
force pump, or painted over the surface with saturated cloths 
tied to the ends of sticks. An automatic oiler may be impro- 
vised by placing a barrel of oil a few feet above the water to 
give the oil the necessary spread, and having a perforation in 
the bottom of the barrel to drop about twenty times to the 
minute. 

The quantity of oil which has been found amply sufficient 
is i ounce for each 15 square feet of surface. It has been esti- 
mated that a barrel of oil costing only a few dollars is suffi- 
cient to cover 96,000 square feet of surface. 

Evaporation, rains, and winds prevent permanent results, so 
that the oiling must be repeated. Intervals of two or three 
weeks are the proper average, and certain days of the month 
should be systematically chosen. . It is best to begin the oiling 
in the spring to prevent the first generations. 

Nearly every antiseptic and poison has been employed for 
the destruction of mosquito larvae. The aniline derivatives 
are valuable, especially that known as Larvicide, which destroys 
also fish and other forms of life which may be useful in killing 
larvae. The same objection applies to Phinotas Oil, a cresol 
combination, and saprol, which are effective larvicides. Forma- 
lin, corrosive sublimate, carbolic acid, and lysol are too slow 
in their effects upon larvae to be of practical value. Perman- 



PROPHYLAXIS 311 

ganate of potash has proved disappointing in all trials made 
of it. Tar, creosote, tobacco, pyrethrum, sulphate of iron, and 
numerous other substances have been used and abandoned. 
Nothing is so efficacious, so free from danger, and so inexpen- 
sive as kerosene. 

Where it is not feasible either to drain or oil a breeding pool 
the introduction of small fish has been practised with success. 
Certain species of fish prey upon the eggs, larvae, and pupae 
of mosquitoes, and even upon adults when about to emerge 
from the pupal shell or when in the act of oviposition. The 
common top minnows (Gambusia and Fundulus) and the sun- 
fish are excellent for this purpose. The former being very 
voracious and top-feeders, are especially adapted for the de- 
struction of anopheles larvae. They are fast breeders and 
resist the drying of pools in a remarkable degree. Sticklebacks, 
gold-fish, and roach are also larvivorous. It is doubtful 
whether the common German carp, on account of its feeding 
habits, is of any use for this purpose. The tadpole is valueless 
for the destruction of larvae. 

The larvae of dragon-flies devour the mosquito larvae among 
other prey. Feeding upon the bottom, however, they are not 
very effective, as to anopheles larvae especially, unless the pool 
be shallow, in which case they may destroy great numbers. 

The water boatman (notonectidcc) is an efficient enemy, and 
many mosquito larvae are cannibalistic among the smaller 
forms, even of the same species. 

The hair worm, a species of mermis, is sometimes a fatal 
parasite of mosquito larvae. During a certain summer Stiles 114 
found that many of the larvae which he collected died in the 
laboratory. Upon dissection he found them infested with the 
hair worm. It was noted that in years when mosquitoes were 
scarce this parasite was plentiful. 

Giles 119 in India found larvae infested by a parasitic stalked 
infusorian, and suspects that they may be the cause of the 
inexplicable disappearance of larvae from places where they 
were formerly abundant. 

Galli-Valerio and de Jongh 82 observed from laboratory and 
field experiments that aspergillus niger and glaucus, especially 



312 THE STUDY OF MALARIA 

the former, exercised a very unfavorable influence upon the 
development of mosquito larvae. 

The cultivation of the water pest (anacharis alsinastrum) , 
which so thickly covers the surface of the water as to prevent 
the larvae and pupae from gaining access to the air, has been 
recommended as a prophylactic measure. It is said that in 
certain localities the disappearance of malaria coincides chrono- 
logically with the appearance of the water pest. 

The natural enemies of adult mosquitoes are few and prac- 
tically insignificant. Dragon-flies, night-hawks, whip-poor- 
wills, swallows, bats, and certain species of lizards destroy a 
number and some are killed by parasitic mites and a small 
suctorial fly. 

An ideal prophylaxis destroys the breeding pools or the 
aquatic stages of mosquitoes, but remedies against the adult 
insects are sometimes necessary. For this purpose a great 
variety of substances has been tried. One of the most primitive 
of measures is the smoldering fire of chips, rags, and feathers, 
to be seen in summer twilight to the windward of nearly every 
negro cabin. 

The most practical means are the -fumes of burning sulphur 
and of pyrethrum powder. The room to be fumigated should 
be made as nearly airtight as possible. 

Of sulphur, from 2 to 5 pounds should be used for every 
1,000 cubic feet of space. Its deleterious effect upon metals 
and delicate fabrics limits its use somewhat. Sulphur dioxide 
fumes have been found to be an excellent insecticide. Rose- 
nau 393 says of it : "Very diluted atmospheres of the gas v/ill 
quickly kill mosquitoes. It is as efficacious for this purpose 
when dry as when moist, whereas the dry gas has practically no 
power against bacteria. Contrary to formaldehyde, it has sur- 
prising powers of penetrating through clothing and fabrics, 
killing the mosquitoes even when hidden under four layers 
of toweling, in one hour's time, and in very diluted proportions. 
This substance, which has been so long disparaged as a disin- 
fectant because it fails to kill spores, must now be considered 
as holding first rank in disinfection against yellow fever, 
malaria, filariasis, and other insect-borne diseases." 



PROPHYLAXIS 



3*3 



The room should be kept closed for several hours to insure 
the complete extermination of the insects. 

Pyrethrum powder may be burned in the proportion of a 
few ounces to a pound for each 1,000 cubic feet of space. It 
may be moistened with water, molded into cones, and dried, 
or the powder may be slightly dampened at the summit with 
alcohol and lighted. The mosquitoes are suffocated by the 
fumes and must be swept up and destroyed. 

Formaldehyde has been tried and found wanting, but may be 
effective when very large quantities are rapidly liberated in 
a tight room with few hiding places for the insects. 

The pulverized leaves and stems of the common jimson 
weed (Datura stramonium) , mixed with saltpeter, and burned 
in the proportion of 5 ounces to 1,000 cubic feet of space, have 
been successfully used by the New Jersey Mosquito Commis- 
sion. 

Chlorine gas, generated by adding a few drams of sulphuric 
acid to an ounce of chloride of lime, is said to be efficient, and 
burning tobacco leaves are useful. 

The following table copied from Celli 80 shows the effects 
of various odors, fumes, and gases upon adult mosquitoes 
according to his experiments : 

Action of culicidal substances on mosquitoes (C. annulatus, 
C. pip pens, A. claviger) : 



I. Odors 

„ , , Time in which death is manifested. 

No. substances used. . . 

Apparent. Actual. 

i. Essential oil of turpentine 1 min. 1 min. 

2. Iodoform 10 min. 40 min. 

3. Menthol 10 min. 45 min. 

4. Nutmeg 10 min. 2 hours 

5. Musk 30 min. 3 hours 

6. Camphor 4-5 min 4-5 hours 

7. Leek 5-10 min. 5 hours 

8. Crushed pepper 20 min. 6 hours 

9. Naphthalene 10-35 min. 8 hours 

10. Roman wormwood 6 hours 24 hours 

1 1. Onion 4-6 hours Survive 

12. Salvia Survive 

13. Rosemary Survive 

14. Dry and fresh basil Survive 

15. Cinnamon bark Survive 

16. Asafetida Survive 



314 THE STUDY OF MALARIA 

II. Fumes 

Time in which death is manifested. 
Substances used. Apparent. Actual. 

1. Tobacco Instantly 1-3 min. 

2. Larvicide Instantly 5 min. 

3. Chrysanthemum powder (unexpanded 

flowers) 5 min. 1 hour 

4. Valerian root 5 min. 2 hours 

5. Fresh leaves of eucalyptus 3-5 min. 3 hours 

6. Quassia wood 16 min. 5 hours 

7. Pyrethrum powder 5 min. 6 hours 

8. Dry leaves of Mentha pulegium 5 min. 8 hours 

9. Pitch 10-13 min. 8 hours 

10. Dry leaves of basil 2-6 min. 24 hours 

11. Dry rosemary 7-12 min. 24 hours 

12. Culicidal cones 2-10 min. 36 hours 

13. Dry chamomile flowers 2-10 min. 36 hours 

14. Dry leaves of Saturgia hortensis 2-10 min. 36 hours 

15. Salvia leaves 8-10 min. 36 hours 

16. Wood 5-7 min. 12-48 hours 

17. Guaiacum resin 12 min. Survive 

18. Myrrh 15 min. Survive 

19. Elemi 15 min. Survive 

20. Incense 15 min. Survive 

III. Gases 

Time in which death is manifested. 
Substances used. Apparent. Actual. 

i. Sulphur dioxide Instantly 1 min. 

2. Hydrogen sulphide Instantly 1 min. 

3. Ammonia 1 min. 2 min. 

4. Illuminating gas 1 min. 2 min. 

5. Formaldehyde (Trillat's apparatus) 2 min. 10-15 min. 

6. Sulphuret of carbon 15-30 min. Survive 

7. Acetylene ... Survive 

Ross' 392 summary is a fitting conclusion to the consideration 
of mosquito destruction : 

Summary of Objects 

1. We do not propose to exterminate mosquitoes in any- 
entire continent. We propose only to deal with them in the 
town in which we live and in its suburbs. 

2. We do not propose to get rid of every mosquito even in 
this town. We aim only at reducing the number of the in- 
sects as much as possible. 

3. We do not think it possible to drain or otherwise treat 
every breeding place in the town. We aim at dealing with 
as many as possible. 

4. We cannot exclude mosquitoes which may just possibly 
be blown into the town from miles away. We content our- 
selves with preventing the insects breeding in the town itself. 



prophylaxis 315 

Summary of Methods 

1. We start work at once with whatever means we can 
scrape together. 

2. We operate from a center outward. 

3. We clear houses, backyards, and gardens of all rubbish, 
empty tubs and cisterns containing larvae, or destroy the larvae 
in them by means of oil. 

4. We show people how to do these things for themselves, 
and how to protect tubs and cisterns by means of wire gauze. 

5. When we have cleared as many houses as we determine 
to deal with we clear them over and over again. 

6. We fill up or drain away all the pools, ditches, old wells, 
and puddles we can — especially those which contain most 
larvae. 

7. Such pools as cannot be filled up or drained are deepened 
and cleared of weeds if they contain larvae. 

8. Streams and water-courses which possess larvae are 
"trained." 

9. Where we can do nothing else we destroy larvae period- 
ically with oil, or by brushing them out with brooms, or by 
other means. 

10. We endeavor to interest our neighbors in the work, and 
to educate the town into maintaining a special gang of men 
for the purpose of keeping the streets and gardens absolutely 
free of stagnant mosquito-bearing water. 

Motto : 

Our motto should be one which, I think, will shortly become 
the first law of tropic sanitation, namely : 

"NO STAGNANT WATER." 

II. MEASURES DIRECTED TOWARD THE DESTRUCTION OF 

PARASITES 

Efforts to destroy the malarial parasites in the human body 
assume two modes. The first consists of the radical cure of 
the malaria-infected individual, the prevention of a relapse, 
thereby benefiting the individual and annihilating a source of 



316 THE STUDY OF MALARIA 

danger to the community. The second mode consists of the 
administration, to persons not necessarily infected, of a drug 
which destroys the parasite soon after the latter is introduced 
into the body, before the incubative stage is completed. 

Cases of latent and atypic malaria (Fig. 94) are of greater 
importance to prophylaxis, being sources of greater danger to 
communities than are typic acute cases. The duration of the 
acute attack is short, the patient is apt to be placed under rela- 
tively favorable conditions and to receive quinine; he does 
not wander and disseminate the disease, and his blood may 
contain but few sexual forms of the parasite. On the other 
hand, the subject of latent malaria may harbor parasites for 
months, and, the condition being unrecognized or ignored, he 
does not take quinine, and is a fountain of infection in diverse 
places and for prolonged periods. 

Koch has maintained that the prompt and permanent cure 
of all acute cases of malaria and the systematic search for, and 
appropriate treatment of, all latent cases in a region will result 
in the extermination of the disease from such a locality. This 
is theoretically possible, but could be practised only in small 
communities under perfect control. Nevertheless, it is cer- 
tainly the duty of physicians to endeavor to effect radical cures 
of the cases which come under their observation, a duty owed 
not only to the patient, but to the public, and such efforts will 
go far toward the eradication of the disease. 

Quinine Prophylaxis. — Theoretically the administration of 
quinine to healthy individuals for the prevention of malaria is 
not an ideal method of prophylaxis, for, strictly speaking, it 
does not prevent infection, but destroys the parasites in the 
incubative stage after inoculation into the human body. But 
no one method satisfies all conditions ; each has its advantages 
and its limitations, and frequently two or more methods must 
be employed simultaneously. 

Quinine prophylaxis is indicated in proportion to the diffi- 
culty of pursuing more permanent methods. It is valuable 
where screens and bars are not available, as in camping, 
marching, traveling, or where the occupation takes one out at 
night. When residents of non-malarial countries go into mala- 




Fig. 94. — Carriers of latent infections are disseminators of the disease. 



PROPHYLAXIS 317 

rial localities, especially in the rural districts, for short spaces 
of time quinine is a most valuable prophylactic. After infec- 
tion is known to have occurred quinine is, of course, essential 
not only as a cure, but as a preventive. It may be employed 
effectively where it is impossible to destroy mosquitoes or as 
an adjunct to other measures. 

Numerous experiences attest the value of quinine in the 
prophylaxis of malaria. 

The observations of Logan, 394 made upon soldiers of the 
Civil War, were as follows : Of 230 men who took no quinine 
134 had fever, a ratio per 1,000 of 582. Of 246 men who took 
quinine irregularly 96 had fever, a ratio per 1,000 of 390. Of 
506 men who took quinine regularly 98 had fever, a ratio of 
193 per 1,000. 

Jilek 86 reports that among 736 soldiers, living under similar 
conditions, 5,000 took 0.10 gram of sulphate of quinine each 
morning and only 18 per cent, had fever, which was mild and 
recurrences few. Among the 236 men who took no quinine 
28 per cent, had fever. 

At Melaboe, in the Dutch Indies, there were, during 1896, 
in the garrison 1,237 days of sickness and 33 men excused 
for malaria; in 1897, 1,841 days of sickness and 44 cases of 
malaria. Beginning with November, 1907, each soldier took 
0.50 gram of quinine twice a week. During 1908 there were 
only 214 days of sickness and no one dismissed on account of 
malaria. 1 

At the prison of Bhagalpur the average mortality had been 
48 per 1,000. With cinchonidine prophylaxis it fell to 9 per 
1,000 in 1895, and to 7.2 per 1,000 in 1896. The civil popula- 
tion suffered heavily from malaria during this time. 1 

During 1901 the malarial morbidity in the Grossetane marsh, 
which was formerly 55 per cent., was reduced to 24.53 P er 
cent. 

In Italy, Mori 79 gave to persons over sixteen years of age 
0.50 gram euquinine daily, and to children 0.25 gram, with the 
result that of these only 6.25 per cent, were attacked, while of 
those who took no prophylactic 81 per cent, took the disease. 

Ziemann 48 observed in Cameroon that among 25 persons who 



318 THE STUDY OF MALARIA 

did not use quinine all were attacked with malaria, with a 
mortality of 36 per cent. Of 69 who used quinine regularly 
according to his method 1 6 per cent, remained free from mala- 
ria, and among those attacked only 4.35 per cent. died. 

Babes 395 employed Koch's method of quinine prophylaxis in 
Roumania. In one locality of 214 inhabitants who took quinine 
prophylactically no case of malaria occurred, while among 32 
who used no preventive there were 1 5 cases. In another local- 
ity, in which 1,800 inhabitants were thus treated, not a single 
case occurred, though in 800 who did not employ the prophy- 
lactic the morbidity was 20 per cent. 

During a severe epidemic in 1907 in Marathon, a highly 
malarial locality, Hadjimichalis and Cardamatis 93 had the fol- 
lowing experience with Koch's method : 

Of 67 persons who took quinine for 21-24 weeks none were 
infected; of 145 who took it for 16-20 weeks 20.6 per cent, 
were attacked; of 220 who took the drug for 11-16 weeks 48.6 
per cent, were attacked; of 820 who took it for 1-10 weeks 
56.5 per cent, were infected. 

The following table shows the effect of quinine prophylaxis 
in the community of Stroppiana : 83 

Y ear Cases of Grams of Quinine 

Malaria. Consumed. 

1903 87 800 

1904 57 2500 

1905 44 4025 

1906 26 5832 

1907 II 4500 

The Society for the Study of Malaria in Italy, beginning 
prophylactic experiments on a small scale in limited areas, have 
extended their practical efforts until the results are felt 
throughout the entire country. 

Quinine has been the chief reliance of this organization. 

The following figures give the malarial mortality in Italy 
from 1900 to 1907: 

Year. Deaths. Year. Deaths. 

1900 IS,86S 1904 8,463 

1901 13,558 1905 7.845 

1902 9,908 I906 4,871 

1903 8,517 1907 4,l60 



PROPHYLAXIS 319 

Malarial admissions to the hospital of Marcianise : 

Year. Cases. Year. Cases. 

1900 6oi 1904 I38 

1901 410 1905 124 

1902 227 I906 112 

1903 126 1907 47 

The distribution of quinine by the Italian Government has 
had a decided effect upon the prevalence of malaria, as evi- 
denced by the following - : 

Number of Morbidity. 

Year. persons. 

1902 3,055 7.7 

1003 19,021 5.6 

1904 52,690 8.0 

1905 59,340 5-8 

1906 110,804 6.4 

1907 100,816 4.1 

The decrease of malaria at Pontepossero and Uniti, the 
result of a "mixed" prophylaxis, screening and quinine, is re- 
markable : 

v Per Cent, of Population 

* ear- Attacked by Fever. 

Before 1902 60.8 

1902 55.0 

1903 • 40.0 

1904 30.0 

1905 16.0 

1906 9.8 

1907 2.0 

Notwithstanding the favorable experiences recorded, there 
are disadvantages in the employment of quinine as a prophy- 
lactic. The obstacles are much greater in its use as a public 
measure than private. 

One objection, varying considerably with individuals, is cin- 
chonism, which may even amount to very unpleasant nervous 
or gastric disturbance. 

To be efficient as a preventive of malaria quinine must be 
taken in sufficient dose during- the entire malarial season. It 
is difficult to make ignorant people realize the importance of 
taking treatment during several months to prevent, maybe, 
merely a chill, and few governments have the authority to 
force them to do so. No permanent results are to be obtained 



320 THE STUDY OF MALARIA 

in this way unless all take the drug throughout the malarial 
season and all cases of malaria are radically cured. 

The expense of public prophylaxis with quinine on a large 
scale is enormous ; in fact, in some instances prohibitory. 
Money spent for quinine to be given in inadequate doses at 
irregular intervals is wasted. 

The size of the dose and the interval at which the prophy- 
lactic is administered are of the utmost importance. Very 
varying quantities have been employed at different intervals, 
but the established methods have about settled down to those 
described below : 

The method canonized by Koch consists in giving I gram of 
quinine every sixth and seventh day, seventh and eighth, eighth 
and ninth, or ninth and tenth day, according to the danger of 
infection. This manifestly leaves several intervening days in 
which there is no quinine in the circulation. In localities, there- 
fore, in which estivo-autumnal malaria is prevalent, the shorter 
interval of administration should be preferred on account of 
the shorter period of incubation of this form of malaria. 

This method has proved very valuable in many hands. 

Ziemann 48 describes his method of "universal prophylaxis" 
as follows: 

i. One gram of quinine is given every four days, three days 
intervening. The drug is given in solution with 5 drops of 
hydrochloric acid. If cinchonism is marked, 1 gram of potas- 
sium bromide is given. 

2. If 1 gram of quinine is not well borne, 1 gram of euqui- 
nine is given. 

3. If this produces too decided cinchonism, y 2 gram of 
quinine is given as above. 

4. If Yz gram of quinine cannot be taken, T / 2 gram of euqui- 
nine is administered. 

The drug is given early in the morning or one and a half to 
two hours after a meal. The rule is to give a dose on the first 
of each month and thereafter on each day of the month 
divisible by four. 

By this method it is believed that quinine is constantly in 
the blood current, and that this result is accomplished with a 



PROPHYLAXIS 321 

minimum amount of the specific necessary for efficient prophy- 
laxis. 

The method of Plehn, 171 ]/ 2 gram of quinine every fifth 
evening, has already borne the test of experience. 

The administration of small doses of quinine daily is the 
oldest method of giving quinine prophylactically. From 1^2 
to 6 grains have been given daily. It is probable that the smaller 
amount is almost entirely a waste, though in Italy 40 centi- 
grams daily is the universally adopted dose and accomplishes 
good results. It is very doubtful, however, whether such doses 
would prevent relapses in those already infected. 

Nocht's method is to give 0.2 gram of quinine five times 
daily. Though said to be efficient, this method is entirely too 
tedious to become popular. 

Doses varying from 0.25 to 0.50 gram given every other 
day or every three days have been recommended with favor- 
able experience. 

A method of giving quinine for the prevention of malaria 
should be chosen by experience in the region. The Koch 
method, every sixth and seventh day, has been satisfactory in 
the writer's hands. 

The best form in which to employ quinine in prophylaxis 
and the size of the dose for children do not differ from those 
in the treatment, and will be considered in that section. 

The use of "bitters," a solution of quinine in whisky, is not 
to be recommended. Such a mixture usually contains too 
little quinine to be of benefit, and the use of whisky in the hot 
season, especially when followed by exposure to the sun, is to 
be condemned. 

Prophylactic quinine should be continued for two or three 
months after leaving a possible source of infection, even if the 
disease has not been contracted, and, in the latter event, for yet 
a longer period. 

The Italian Government has undertaken the sale of quinine 
at a low price and its free distribution. 

The law of December 23, 1900, authorized the Minister of 
Finance to sell publicly the hydrochlorate and the sulphate 
of quinine through the pharmacies, tobacco offices, etc. These 
21 



322 THE STUDY OF MALARIA 

preparations are sold in the form of tablets of 20 centigrams, 
and the price of a tube containing ten tablets is, for the hydro- 
chlorate, 40 centimes, and, for the sulphate, 32 centimes. 

The law of November 2, 1901, prescribes that laborers are 
to be furnished gratuitously with quinine. The law considers 
malaria as a disease from which the landlord should protect the 
laborer, and the quinine is furnished by or charged to the land- 
lord. If the laborer dies of pernicious malaria and it is evident 
that death was due to a lack of quinine, the family of the 
laborer is entitled to indemnity from the landlord. Govern- 
ment employes in malarial localities receive free quinine from 
the Government. 

Combinations in pill form of quinine, iron, and arsenic, 
known as antimalarial pills, are valuable as tonics and are 
mildly prophylactic. They do not, however, contain sufficient 
quinine to be reliable prophylactics, at least in this region. 
Such pills, Grassi's esanophele pills, were tried in comparison 
with the sulphate and hydrochlorate of quinine by the Italian 
Antimalaria Society and found to be less efficient. 147 

Arsenic, so long vaunted as an antimalarial, has been thor- 
oughly tried and abandoned. 

Narcotine has some prophylactic value, though, as evident 
from the experience of Duncan, 396 it does not compare with 
quinine. In 1896, 50 men taking 3 grains of quinine had no 
cases of malaria; 50 taking 2 grains of narcotine had 3 per 
cent, of malarial cases, while those taking no drug had 6.5 per 
cent, of malaria. In 1897, 50 men taking 3 grains of quinine 
had no malaria, 50 taking 2 grains of narcotine had 6 per cent. 
of malaria, while those taking no drug had 9.8 per cent, of 
malaria. 

Tea, coffee, and lemons have very slight preventive virtue. 

III. MEASURES TO PREVENT THE ACCESS OF MOSQUITOES 
Exclusion of Mosquitoes. — The prophylactic value of ex- 
cluding mosquitoes is in proportion to the number of anophe- 
lines and the proximity of infected persons. 

A properly protected house should have every door and 
window screened. In some localities it is advisable to cover 




Fig. 95. — The screened vestibule as employed by the Italians (Celli). 




MBBb^mBmBBEBBBB 

Fig. 96. — A model of house screening 





Fig. 97. — The importance of screens is appreciated by the shanty boatman. 




Fig. 98. — Improper size of mosquito Fig. 99. — Proper size of mosquito 
netting. netting. 



PROPHYLAXIS 323 

even the chimneys with wire netting. Doors should be pro- 
vided with springs to necessitate closure. Where mosquitoes 
are plentiful, and a door is much used, a double door, with an 
intervening vestibule, after the manner of the Italians (Fig. 
95), is to be preferred. A screened porch permits of sitting 
in the air in the evening when it would be dangerous to do so 
otherwise. 

The selection of the gauze for screens is of the highest 
importance. The mesh of the wire netting often used. No. 12, 
is too large, permitting small mosquitoes to pass (Figs. 98 
and 99). None should be used with fewer meshes than 18 
to the inch. In the absence of wire gauze, cotton mosquito 
netting may be employed, but, being frail, soon becomes torn 
and useless. 

Persons whose ocupations keep them out at night in highly 
malarial places, as watchmen and others, should be protected 
with veils and with leather gloves having gauntlets. 

The mosquito bar is indispensable in malarial countries. Be- 
sides being very effective when properly adjusted, it is the 
most inexpensive of all prophylactic methods. 

Stephens and Christophers 113 relied personally almost en- 
tirely upon the protection afforded by the mosquito bar. They 
say: "The net should be square (not a bell net) ; should not 
have a single, even minute, hole ; should hang outside the poles, 
if these are used; should be tucked under the mattress, and 
should not trail on the ground. A piece of closely woven mate- 
rial, fastened on all round at the level of the body, is a neces- 
sary addition in order to protect the limbs during sleep from 
bites through the net. When not in use the ends of the net 
should be twisted up somewhat and then thrown over the top. 
We always arranged our nets ourselves, never trusting to ser- 
vants, and, further, to be doubly certain, we always carefully 
searched the interior with a candle before going to sleep. To 
these minute precautions solely we attribute our absolute free- 
dom from malaria. Employed without care and attention a 
mosquito net is of little protection in such malarious places as 
most up-country African stations." 

The Public Health and Marine Hospital Service issues the 



3 2 4 



THE STUDY OF MALARIA 



following instructions in regard to screening against mos- 
quitoes : 397 

i. The netting used should have meshes fine enough to 
prevent the passage of mosquitoes (at least 18-20 to the inch). 

2. It is important to screen the windows and doors of the 
house. It is doubly important to screen the beds of fever 
patients. 

3. Mosquitoes can bite through the mosquito nets when any 
part of the body is in contact with the netting. 

4. Frequent examinations should be made to see that there 
are no torn places in the netting or that no mosquitoes have 
found a lodging inside. 

5. The netting should be well tucked in to keep mosquitoes 
from entering. 




v>^ 



Fig. 100. — British experimental hut near Ostia (Manson). 

6. If mosquitoes are found within the netting they should 
be killed inside, and not merely driven or shaken out. 

The results obtained from mechanical prophylaxis have been 
very satisfactory. The celebrated experiment of Sambon and 
Low 398 is striking. Under the auspices of the English Colonial 
Office and the London School of Tropic Medicine these scien- 
tists spent the entire malarial season of 1900 near Ostia, in one 
of the most malarial parts of the Roman Campagna. The hut 
in which they lived was constructed in London for the purpose, 
and was thoroughly screened. They drank the same water and 
worked in the marsh with the natives. They took no quinine, 
and, in fact, observed no prophylactic precautions excepting to 



PROPHYLAXIS 325 

remain in the house from sunset to sunrise. Though malaria 
and anopheline mosquitoes were abundant about them, they re- 
mained the entire season without becoming infected with 
malaria. 

The following figures show the results obtained by the Italian 
Society for the Study of Malaria. 147 Of 802 persons incom- 
pletely protected 10.9 per cent, had primary infections; of 
5,165 protected more or less completely there were 3.3 per 
cent, of primary infections ; while among 4,363 persons com- 
pletely protected there were only 1.9 per cent, of primary in- 
fections. Among unprotected persons in the same regions the 
proportion varied between 40 to 60 per cent. 

The following experiment was conducted by the Japanese 
military authorities upon the Island of Formosa. A company 
of 115 men was completely protected against mosquitoes, with 
the result that not a single case of malaria occurred in the 
company. The rest of the battalion, numbering 646 men, was 
unprotected, and 282 cases of malaria, with a mortality of 1.12 
per cent., occurred among them. 86 

At the custom-house barracks at Porto- Vecchio there were 
in 1901 among 23 persons 14 cases of malaria. In 1902, after 
the installation of metal screens, there was not a single case in 
the same force. 86 

In one of the most insalubrious localities in Corsica there 
were in 1904 among 153 individuals 80 cases of malaria. 
Screens were put up in 1905, and during the year there were 
only 7 primary cases. 

Schoo's 90 results with screening in Holland were favorable. 
Among 47 inhabitants there were 18 cases of malaria in 1901. 
Screens were installed March, 1902, and not a single fresh 
infection occurred. Of 58 unprotected persons there were 8 
cases of malaria in 1901, and in 1902 there were 19 cases. 

As with every other method for the prevention of malaria, 
screens have certain shortcomings. It is evident that if malaria 
is to be eradicated by these means from a locality every house 
should be screened, otherwise only those in the protected houses 
would be exempt, and only so long as they remain in such 
houses. It is out of the question in many malarial places to 



326 THE STUDY OF MALARIA 

consider the screening of all the houses, both on account of 
the expense and because of the poor construction of many of 
them, permitting mosquitoes to enter through crevices and 
other openings. The fact that screens offer a slight hindrance 
to the free circulation of air in hot countries is of little moment 
in the face of the benefits derived from their use, and they 
must be considered as one of the most effective means of 
private prophylaxis. . 

Of local applications to drive away mosquitoes many sub- 
stances have been tried, particularly the essential oils, of which 
the oils of citronella, eucalyptus, and lavender are probably the 
most efficacious. Petroleum, infusion of quassia, naphthaline, 
powdered sulphur, camphor, garlic, the oils of cloves, tar, 
pennyroyal, chrysanthemum, and anise have been employed 
with varying degrees of success. 

The following preparations are highly recommended : 

Cedar oil 1 ounce ; 

Oil of citronella 2 ounces ; 

Spirits of camphor 2 ounces. — M 

Sig. : Apply a few drops to a cloth and hang upon the bed 



12a 



Alcohol "'} »'— ; 

Oil of lavender 1 dram. — M. 

Sig. : Apply to the skin. 122 

Quinine-glycerine 1 : 1000 

Sig. : Apply to the skin. 48 

AlcSol} « 5.0 

Aq. colomensis, 1 M 

Ol. eucalyptus J 

Tr. pyrethrum 15.0. — M. 

Sig. : Dilute with four or five parts of water and apply to 
the skin. 48 

For the local relief of mosquito bites, touching with water 
of ammonia or with glycerin are efficient. 

In India the punka is employed to keep the air in motion, and 
for this reason is found to be of service in driving away mos- 
quitoes. The electric fan has this effect also, but for obvious 
reasons should not be employed for this purpose during sleep. 

The value of smoke against mosquitoes is well known, 
though it is not always entirely effective. The writer recalls an 
occason while on an island off the Gulf coast of Florida where 



PROPHYLAXIS 327 

smoke was of no avail against the terrific onslaught of blood- 
thirsty mosquitoes, and it became necessary to bury himself up 
to the neck in the sand and to cover the head with a coat. 

Isolation of the malarial patient is as truly indicated as in 
yellow fever, both diseases being conveyed in the same manner. 
Mosquitoes must become infected before they can infect man; 
breaking the vicious circle at this point would extirpate mala- 
ria. Isolation is demanded not only for the good of the com- 
munity, but to prevent reinfection of the patient, who should 
be confined under a well-adjusted bar until a radical cure is 
effected. It is not to be expected, however, that as much can 
be accomplished from the isolation of malaria as from isola- 
tion of yellow fever. Many cases of malaria entirely escape 
medical treatment, and a malarial subject may be a source of 
infection for a year or more, while yellow fever is infectious 
for only a few days. 

Since it has become evident that so great a proportion of 
the inhabitants, especially the children of tropic countries, 
harbor malarial parasites in the blood, segregation of the 
whites from the natives has been proposed and in some in- 
stances practised with success. While the question is of some 
import in this country, the negro quarters in most of our 
towns are fairly well defined from those of the white. Upon 
the premises the householder should see that his servants' 
quarters are as thoroughly screened as his own. In the choice 
of camp sites native houses should be avoided beyond the 
limit of flight of mosquitoes, if possible. 

Great good is being accomplished in the prophylaxis of 
tuberculosis by education, keeping the main facts in the etiology 
and prevention constantly before the eyes of the people. So 
much cannot be expected for malaria on account of the igno- 
rance and carelessness of the class and race of people most 
scourged, but undoubtedly some good may accrue from this 
method. The Europeans, at home and in their colonies, have 
obtained some results in the prophylaxis of malaria by teach- 
ing the people the elements of the cause and prevention of 
the disease. 

Lectures, illustrated by stereopticon views, are held publicly. 



328 THE STUDY OF MALARIA 

Publications in simple language, in the form of circulars and 
tracts, and even appropriately illustrated postcards are scat- 
tered broadcast. The Italian Society for the Study of Malaria 
has distributed about two millions of these circulars. The 
principles of prophylaxis are instilled into the minds of the 
school children, and made attractive and impressed by means 
of illustrated charts. The lay press has been used to advan- 
tage. With such means the formation of an antimalarial 
league can do much for a community. A little can be accom- 
plished by education, and this little should not be neglected. 

Schools and departments of tropic medicine have done a 
great deal to disseminate a knowledge of this very important 
subject, and even more stress should be laid upon this impor- 
tant branch of medical science. 

To be thorough, malarial prophylaxis should be handled 
by the Government. Destruction of the breeding places of 
the mosquitoes, which is by far the most radical method, is, 
in many instances, too expensive to be done by individuals. 
The formation of drainage districts, the expenses of which are 
paid by those benefited, is an effective plan, and so enhances 
the value of real estate, from both agricultural and sanitary 
standpoints, that there should be no opposition. The writer 
is convinced that these districts, which are being formed in 
various parts of the South, are decreasing the malaria in a 
decided degree. It is highly probable that malaria will be 
exterminated as a natural consequence of the drainage of the 
soil before the Government or the people are educated to 
the point of taking prophylactic steps. Governments will 
spend millions of money in the eradication of malaria from 
foreign laborers in order to further gigantic commercial enter- 
prises, but make no prophylactic efforts against the malaria 
undermining the vitality and destroying the lives of citizens. 
Individuals who should know better permit anopheles mosqui- 
toes to breed at their doors and to have access to their houses, 
and allow their malaria to go untreated. 

The International Congress of Hygiene at its Brussels 
meeting, September, 1903, recommended to all Governments 
the adoption of the following measures : 144 



PROPHYLAXIS 329 

1. All officers, administrators, or employes before entering 
the service of the country should give proof of a knowledge 
of the epidemiology of malaria and its practical application. 

2. In all countries, places of instruction, depending upon 
either the Government, missions, or otherwise, are urged to 
include in the curricula a teaching of the knowledge of the 
propagation of malaria, and the practical applications which 
proceed therefrom. 

3. Officers, administrators, or employes ignorant of these 
facts or persistently refusing to apply them are to be consid- 
ered unfit for service in malarial countries. 

The almost miraculous results in the prophylaxis of malaria 
which may be obtained by a willing and wealthy Government 
are exemplified in the sanitation of the canal zone previously 
referred to. The means of accomplishing this end are thus 
briefly described by Busck : 399 

"In the beginning the land is cleared by the removal of all 
brush, undergrowth, and grass ; only shade and fruit trees are 
left, and these are thinned out to admit sunlight and free 
ventilation. Where possible, swamps and lowlands are filled 
in, the immense excavations at the Culebra cut furnishing 
abundant material. Then the whole area is drained to carry 
off the surface water or any constant flow from springs or 
seepage from the hills. This drainage is extended to all new 
work in the canal cut and to railroad work or dumps near 
settlements. The drainage is accomplished by subsoil tile- 
drains, open ditches, and open concrete or stone and cement 
ditches. Drain tiling or cement ditches are made where pos- 
sible, as they require very little care afterward, while the open 
dirt ditches must be constantly cleaned and regraded to pre- 
vent 'pocketing' and the consequent formation of breeding 
pools for mosquitoes. In open dirt ditches the algae will form 
in two or three days after cleaning, and to prevent this drip 
cans are placed at the head of those ditches with a solution 
of sulphate of copper, 5 pounds to a barrel of 50 gallons of 
water. This is also used in all running streams after the 
removal of algae. 

"Open ditches in which the water flows sluggishly have oil 



330 THE STUDY OF MALARIA 

drip-cans at their heads. The oil cans are raised three feet 
above the water to give a wide spread to each drop, and are 
arranged to drop about 20 drops to the minute. The oil used 
is a rather heavy dark grade, which costs the department $4.34 
a barrel. About 3,200 barrels of oil were used within the last 
year. 

"All streams are kept free from algae and are kept within 
restricted banks as far as possible ; this is done by blowing out 
the rapids or falls to produce a uniform flow, and the edges 
are filled in by hand. 

"All swamps, pools, or even temporary collections of water 
are oiled at least weekly, and in the rainy season oftener; 
this applies to the smallest collection of water, even animal 
tracks, ruts from wagon wheels, and crab holes. It entails a 
great amount of work, which is done by colored labor under 
continual supervision. 

"All receptacles holding water must be screened or oiled. 
Water barrels are screened by covering with a board with a 
small, screened opening in the center for the inflow. Below 
this board are two screened holes for the overflow, and the 
water is drawn from a faucet at the bottom. Buckets and 
pails in daily use in a household are not permitted to stand 
filled more than twenty-four hours. All tin cans, bottles, etc., 
must be buried. No gutters are allowed on houses. There is 
a daily inspection of all water receptacles, and weekly the 
inspector at the head of the station must make a personal 
inspection and report any receptacle found containing mosquito 
larvae. The second offense, after a warning, means the arrest 
and fine of the householder. 

"All old machinery, which is found in great quantity all over 
the zone canal, left from the French occupation, is drained 
by punching holes in any part that will hold water or, where 
this is not possible, such places are filled with dirt. 

"Even patent car couplings on the trains in use must be 
inspected and oiled, as they are often found to contain mos- 
quito larvae. 

"When any house or camp is found to contain any number 
of mosquitoes it is fumigated with sulphur by the dry method. 



PROPHYLAXIS 331 

All cracks or openings are pasted over with paper; enough 
pots, each containing 5 pounds of sulphur, are placed at inter- 
vals on the floors to make about 1 pot for each 1,000 cubic 
feet of space. After fumigation the house is left closed from 
three to four hours. 

"All barracks, whether for black or white laborers, bachelor 
quarters, married quarters, offices, churches, lodge-rooms, and 
other rooms used for sleeping, living, or eating quarters are 
screened. The Sanitary Department is responsible for all re- 
pairs of this screening, and employs a large force of carpenters 
for this purpose. 

"The physicians in each district make a weekly report on 
the number of cases of malaria in the different camps; these 
reports are tabulated in the central office of the Sanitary De- 
partment and compared with the previous records, and if an 
increase of even a fraction of 1 per cent, is shown for any 
locality the local inspector is telephoned and ordered to locate 
the point of infection and eradicate the breeding places. Long- 
continued statistics show how nicely this system works. If 
any more serious increase occurs a special mosquito inspector 
is sent out from the central office to locate the trouble and 
report on the best measures to be taken. 

"The difficulties of this work are numerous. The constant 
increase of population requires new sites for camps to be 
made in the unimproved, brush-covered country; the ever- 
changing conditions due to the canal work are a continued 
source of trouble; the progress of each steam-shovel or of 
each of the extensive dumps produces new problems to be 
solved in the way of drainage, and, above all, the recurring 
deluges of the rainy season cause rising creeks and rivers and 
overflow of lowlands so irregular as to be impossible to fore- 
see. 

"The Sanitary Department has, aside from its office force, 
about thirty sanitary inspectors and employs between 1,200 
and 1,300 laborers. The total cost of the Sanitary Inspector's 
Department is between three and four hundred thousand dol- 
lars." 

It should be the duty of the authorities of every malarial 



332 THE STUDY OF MALARIA 

country to remove the duty from quinine and to maintain a 
high standard of purity and a low price. 

In military practice permanent quarters should be properly 
screened, and all breeding pools within the radius of danger 
should be destroyed. . Temporary quarters should be chosen 
with reference to the breeding of mosquitoes, and the force 
should, if necessary, be subjected to Koch's quinine pro- 
phylaxis. Ships should not anchor too near the shore of 
malarial localities. 

Private prophylaxis consists of measures having reference 
to the person and to the premises. Personal prophylaxis is 
synonymous with proper hygiene. Suitable food, water, and 
clothing are essential. Regular hours must be kept, and con- 
stipation, chilling of the body, and excesses of all kinds must 
be avoided. Prophylactic quinine is not constantly necessary 
for residents if the premises are in proper condition, but is 
suitable for strangers and under conditions where mosquitoes 
cannot be excluded. Persons sleeping upstairs are less liable 
to infection than those upon the first floor. 

Pools are to be filled, drained, or oiled, and vessels emptied. 
It has been suggested that a tub of water be kept on the place 
to tempt mosquitoes to breed, and that this be emptied every 
few days. Stock ponds should be drained, oiled, or stocked 
with fish. The houses should be thoroughly screened, and 
where these are not effective, or if infection occurs, bars must 
be employed. 

PROPHYLAXIS OF HEMOGLOBINURIC FEVER 

A. Plehn has shown that hemoglobinuric fever is prevent- 
able to a greater degree even than malaria. In 1897-99 among 
the officers of Cameroon who used no prophylactic there oc- 
curred in 578 months of residence 287 cases of malaria and 
31 of blackwater fever, or 1 malaria case for every two 
months and 1 of blackwater fever for each 18.5 months. Ten 
per cent, of the blackwater cases terminated fatally. During 
the same period among those who used prophylaxis there were 
in 446 months of residence 90 cases of malaria and 6 of hemo- 
globinuric fever, or 1 case of malaria for each five months 



PROPHYLAXIS 333 

of residence and i of hemoglobinuria fever for each seventy- 
four months, none of which were fatal. Thus, while malaria 
was reduced by half, the morbidity of blackwater fever was 
lowered to one-fourth. The lowered mortality of these cases 
is even still more remarkable ; similar results were observed by 
Moffatt. 253 Even Koch 90 believes that through appropriate 
quinine prophylaxis not only malaria, but blackwater fever in 
an overwhelming majority of instances can be exterminated. 

The prophylaxis of hemoglobinuric fever consists of the 
prophylaxis and proper treatment of malaria. There are two 
chief methods in vogue for the use of quinine as a preventive 
of hemoglobinuric fever: Plehn's method, j/ 2 gram every 
fifth evening, and Koch's, i gram on two successive days. 

The results of A. Plehn, recorded above, were obtained 
with y 2 -gv3.m prophylaxis, but Ruge 158 maintains that better 
consequences follow Koch's method, and gives the following 
figures: According to the 1903 statistics of Cameroon, there 
were among those who used quinine regularly 12 cases of 
blackwater fever, of which 8 employed the Plehn method, 3 
first Plehn's, then Koch's, and only 1 Koch's method regularly. 
Of 35 cases among irregular users 17 employed the ^2-gram 
method and only 3 the i-gram method. From these figures it 
is evident that Koch's method is preferable even when not 
systematically employed. 

It is necessary to persist in prophylaxis not only while in 
the blackwater fever district, but for several months there- 
after. As a majority of the first cases occur from the second 
to the fourth year of residence, it is evident that greater care 
should be exerted during this period. 



CHAPTER IX 

TREATMENT 

The use of cinchona, whose discovery, made by an uncivil- 
ized people, was one of the most valuable in the history of 
medicine, was at first bitterly opposed by the medical profession. 
Sydenham, Morton, and Torti had in a measure removed the 
prejudice against the drug when the work of Johnson, 16 the 
most pernicious medical book of the nineteenth century, ap- 
peared and largely undid their teaching. After much suffering 
and waste of life quinine has come to be regarded as almost 
specific for malaria. 

The word "almost" is used intentionally, for, while quinine 
is more nearly specific than any other known drug, it has limita- 
tions. While the clinical manifestations of malaria usually 
subside readily after quinine, a radical cure is sometimes diffi- 
cult. A few grains a day will relieve many cases, though a 
dram a day will not save some patients. A few of the sequelae 
of malaria are but little, if at all, influenced by quinine. 

Among the alkaloids of cinchona bark quinine is the one 
now generally used. The following table shows the alkaloidal 
strength of the various salts of quinine, as well as their solu- 
bility : 



Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 
Qu 

Euqu 



c ,. Per Cent, of Solubility in Parts 

Salt - Alkaloid. of Water. 

ne, anhydrous ioo i,750 

ne acetate 84 Slightly 

ne bimuriate (or acid hydrochloride)... 71 Less than its weight 

ne bisulphate 59 8.5 

ne citrate 67 820 

ne hydrobromide 76 40 

ne lactate 78 10 

ne hydrochloride 81 18 

ne salicylate 68 77 

ne sulphate 74 720 

ne tannate, about 30 800 

ne valerianate 76 53 

nine 81 12,500 

334 



TREATMENT 



335 



The duration of malaria under quinine treatment has been 
considered. Acute infections are usually more amenable than 
chronic, though it has been repeatedly observed that it requires 
less quinine to control the paroxysms after the lapse of four 
or five than when the specific is given early in the attack. 

Absorption and Elimination of Quinine. — Most of the 
salts are readily absorbed from the stomach. It has been 
shown, however, that the tannate is more largely absorbed 
from the small intestine. 




Fig. 101. — Average results of the quantitative determination of the excretion of quinine 

in the urine (after Mariani). 

The rapidity of absorption varies with the different salts, 
and is estimated by the length of time required to appear in 
the urine. The time from the administration of the drug until 
it begins to appear in the urine is represented as follows : 

Hydrochloride IS minutes 

Bisulphate 30 minutes 

Sulphate 45 minutes 

Acetate 30 minutes 

Citrate 30 minutes 

Tannate 3 hours 



336 THE STUDY OF MALARIA 

The method of administration of quinine also influences the 
rapidity with which it is absorbed. 

Given by the mouth, a highly soluble salt will begin to 
appear in the urine within fifteen to thirty minutes, and is 
eliminated in the greatest quantity within three to twelve hours. 

Mariani 84 thus tabulates the results of his experiments : 

Contents of each individual portion of urine. Date of successive 
emissions of urine. 

v 'a? 

tn tn tn 

Form and mode of administration. 3 3 3 . ^ „; S J 3 !™' 2 2 

u u u 3 3^,3 3.^3 3 

■g '3 •£ 3 3 3 o o'Soo'S o o 

& O O O A A~So J3 i-g, A A 

u-> o 10 "* ~ in t'3 *o oo'S o « 

M CO rfM fO O M e* CO *3"^-' *0 t» 

Muriate of quinine, 25 per 

cent, solution, subcuta- 

neously 1 3 5 12 24 18 25 7 1 

Muriate of quinine, 1 per 

cent, solution, in spring 

water 1 4 5 12 24 20 16 5 2 1 

Muriate of quinine, I per 

cent, solution with 200 

cc. carbonated water... 1 4 4 8 15 19 30 12 2 1 
Muriate of quinine, 1 per 

cent, solution with 150 

cc. spring water, by 

rectum 1 4 9 16 16 14 9 2 

Muriate of quinine, 1 per 

cent, solution with 150 

cc. carbonated water, in 

an hour another 150 cc, 

by rectum 1 5 5 10 19 28 15 5 4 

Bisulphate of quinine, with 

sugar of milk and 

sodium bicarbonate, by 

mouth 1 2 6 14 26 19 16 6 2 

Carbonate of quinine, by 

mouth, with 200 cc. 

carbonated water 1 4 4 10 12 22 15 12 10 3 

Sulphate of quinine, by 

mouth 5 6 13 25 18 15 8 4 1 

Acetate of quinine, by 

mouth 2 5 6 13 27 16 12 8 3 

Citrate of quinine, by 

mouth 1 4 7 15 29 14 10 7 4 1 

Chinoidin with gum ara- 

bic, by mouth 8 10 38 22 8 5 2 

Tannate of quinine 1 2 9 28 14 4 2 2 

Pulverized bark, sus- 
pended in water 2 3 4 9 6 3 1 

With reference to the influence of food in the stomach upon 

the rate of absorption, Kleine's 400 experiments tend to show 

that quinine is much more slowly absorbed from a full than 

from a fasting stomach. The minute researches of Mariani 

prove, however, that, while the presence of food in the stomach 



TREATMENT 



337 



retards the absorption of quinine during the first- six hours 
after administration, the quantity absorbed during the entire 
twenty-four hours after administration is greater from a full 
than from an empty stomach, and is absorbed in greater quan- 
tities even during the second and third days. He explains 
this by the theory that the liver is able to dispose of only a 
small quantity of the alkaloid when it arrives together with 
the products of digestion. 

Giemsa and Schaumann 300 investigated the subject, with the 
following results : After the administration of I gram of 
quinine upon an empty stomach the excretion by the urine 




Fig. 102. — Excretion of large doses of quinine (after Kleine). 

Quinine muriate, i.o, by mouth, empty stomach. 

Quinine muriate, 2.0, in enema. 

Quinine muriate, 2.0, by mouth, three hours after eating. 



— . — . — . — Quinine muriate, 0.5, subcutaneously. 

during the first twenty-four hours reached 23.6 per cent. ; the 
same amount administered during a meal was followed by 
the excretion of 22.7 per cent, during the first twenty-four 
hours. The quantity excreted during three days after the 
administration of 1 gram upon an empty stomach was 38.93 
per cent. ; during the same period following 1 gram at meal 
time the quantity excreted was 39.8 per cent. 

These investigators found that the elimination of quinine 
by the urine is about one-sixth greater when administered in 
five daily doses than in a single dose. The results of their 
experiments are thus tabulated: 

22 



338 



THE STUDY OF MALARIA 



Table I 

One gram daily of quinine hydrochloride in water, at a single dose, by 
mouth. 

No. Patient. 



Total 

First day 18.5 26.0 

Second day 20.8 28.5 

Third day 19.0 29.5 

Fourth day 19.8 29.8 

Fifth day 19.2 29.6 

Sixth day 20.4 27.4 

Seventh day 29.9 

Eighth day 28.4 

Ninth day 28.6 

Tenth day 29.6 

Average 19.6 28.7 



3. 4. 5. 6. 

quantity of urine excreted in per cent. 
31.5 8.5 24.4 24.8 



32.4 
33-2 
42.2 
24.2 
29.4 
30.6 



29-3 



29.2 
27.4 
27.2 
24.2 
26.2 



12,5 

1 0.0 
18.3 

18. 1 
12.2 
12.8 
154 
15-0 



13.6 26.4 



25-5 
25-9 
14.4 
18.4 
14.2 
24.2 
24.9 



21.5 



26.5 
28.5 
28.0 



27.6 



Total average, 23.8 per cent. 
Remarks. — In patient No. 4 the feces were examined, in which only a 
trace of quinine could be detected with the thalleo-quinine reaction. 

Table II 

One gram daily of quinine hydrochloride in wafers, .2 gram every two 
hours. 

No. Patient. 



First day . . 
Second day 
Third day . 
Fourth dav 
Fifth day . . 
Sixth day . 
Seventh day 
Eighth day 
Ninth day . 
Tenth day . 
Average 

Total average, 27.8 per cent. 
Remarks. — In patient No. 8 the urine of second, third, and fourth days 
were thrown out by mistake. In patient No. 3 the feces were examined : 
only traces of quinine could be detected by the thalleo-quinine reaction. 

While it is a widety prevalent belief that the soluble salts 
of quinine are much more rapidly and completely absorbed 
from the stomach than are the insoluble preparations, experi- 
ments show that such is not the case. 

Mariani 84 records his results as follows : 

Administered on an On a full 

empty stomach. stomach. 

Per cent. Per cent. 

Easily soluble quinine salt 36.28 44-45 

Hardly soluble quinine salt 45-50 68.43 



I. 


2. 


3- 


4- 


5- 


6. 


7- 


8. 






Total quantity of urine 


excreted 


in per cent. 






16.8 


14-3 


I4.4 


18.8 


149 


16.6 


18.9 


l6.0 


28.9 


31-8 


26.9 


32.0 


26.I 


30.1 


34-5 




29.2 


29.7 


26.8 


32.1 


24.I 


30.4 


354 




29.4 


33-8 


29.I 


29.2 


24.I 


30.3 


35-0 




30.1 


33-9 


29.2 


28.0 


28.2 


29.2 


32.8 


29.9 


27-3 


32.9 




29.4 


27.9 


31-4 




30.2 


27.1 


29.0 




29.4 




29.2 




30.4 




29.8 




29.9 




28.1 




29.I 




33-2 












29.4 




33-0 












28.6 



27.0 



30.1 



25.2 



28.6 



24.2 



28.1 



3i-3 



27.6 



TREATMENT 



339 



Giemsa and Schaumann 300 observed that the average per- 
centage excreted within the first twenty-four hours after ad- 
ministration of a soluble salt of quinine was 22.9 per cent., 
while with an insoluble salt it was 24.33 per cent., and they 
conclude that the salts of quinine, hardly soluble in water, are 
at least as energetically absorbed from the digestive tract as 
the soluble ones. 

The results of clinical experience with euquinine and the 
tannate of quinine fully support such a conclusion. 

Briquet and Quevenne 401 formerly maintained that the ab- 
sorption and excretion of quinine proceeded one-sixth more 
rapidly in females than in males. This conclusion, as yet un- 
confirmed, should be determined only after a long series of 
experiments. 

Employed hypodermically the rapidity and thoroughness of 
absorption depends upon the solubility of the salt and the con- 
centration of the solution. The latter is of the utmost impor- 
tance, since, no matter how soluble the salt, if given in strong 
solution it will not be absorbed. 

In order to determine the effect upon human blood and 
serum of quinine injections, Giemsa and Schaumann 300 added 
to 1 cc. of light red human serum 1 cc. of solutions of different 
strengths of various salts of quinine. Their results were as 
follows : 



Preparation. 



Strength of 
solution. 



Contents 

equivalent Behavior of the mixture, 

to anhydrous ,. 

quinine Immediately. After twenty-four hours, 

(per cent.). 



Sulphate 1 : 160 

Bisulphate 1 : 12 

Hydrochloride 1 : 35 

Bimuriate 1:2 

Bimuriate with urea. 1 : 2 

Bisulphate 1.69 : 50 

Hydrochloride 1.22 : 50 

Bimuriate 1.22 : 50 

Bimuriate with urea 1.69 : 50 



.45 Cloudiness. 
4.92 Marked precipi- 
tation. 



2-33 

40.8 

29.61 

2.0 
2.0 

2.0 
2.0 



Marked 
ness. 



cloudi- 



Clear coagulum, 
gray colored. 

Clear coagulum, 
gray colored. 

Cloudiness. 

Marked cloudi- 
ness. 

Cloudiness. 

Cloudiness. 



Precipitation. 

More decided 
precipitation, 
gray colored. 

Increased pre- 
cipitation, co- 
agulation. 

Cloudy gray co- 
agulum. 

Cloudy gray co- 
agulum. 

Precipitation. 

Precipitation. 

Precipitation. 
Precipitation. 



34-0 THE STUDY OF MALARIA 

These investigators claim that coagulation and precipitation 
always follow the injection of concentrated solutions of quinine 
into the tissues, and that this accounts for the slower absorp- 
tion. 

The rate of excretion after injection of solutions of bimuri- 
ate of quinine, i gram to 10 cc. of water and i gram to I cc. 
of water, is recorded in the following tables, respectively: 



Total daily elimination estimated in per cent. 
of anhydrous quinine. 

Number of patient. 



1 : 10— 1 * J 

One day 21.0 24.1 19.8 

Two days 26.2 24.9 22.0 

Three days _^_ 26.9 

Average 23.6 25.3 20.9 

Average of 3 cases, 23.3 per cent. 



1 : 1 — 

One day 10.3 12.1 8.3 

Two days 16.3 15.1 5.2 

Three days 18.2 19.3 2.2 

Average 14-9 15-5 5-2 

Average of 3 cases, 11.8 per cent. 

Mariani 84 found that after the injection of 1 gram of the 
bimuriate of quinine dissolved in 10 cc. of water the maximum 
excretion occurred between the sixth and the twelfth hours, 
while after the injection of the same quantity of the salt dis- 
solved in 2 cc. of water this period occurred between the ninth 
and the eighteenth hours. 

As compared with the oral administration of quinine the 
hypodermic method has been ascertained to be followed by 
the absorption of a smaller proportion of the drug. The pro- 
portion is, according to Giemsa and Schaumann, 300 38.5 : 17.5; 
according to Mariani, 45.63 : 3 1.86, and according to Schmitz, 402 
27.7: 1 6. 1. 

On account of the fact that a portion of the quinine injected 
remains at the site of injection, the period of absorption and 
elimination extends over a longer period, and the drug has 
been detected in the urine a week or more after injection. 

After intravenous administration quinine has been detected 



TREATMENT 341 

in the urine in ten minutes. In a small series of observations 
Mariani 84 found the average daily elimination after intrave- 
nous injection as follows : 

Per cent. 

First day 20.54 

Second day , 6.33 

Third day 1.07 

Injected into the rectum quinine appears in the urine in 
twenty to twenty-five minutes. On account of the tenesmus 
which quinine solutions are prone to produce when introduced 
into the rectum, experiments are not very numerous, but those 
performed show that the drug, even in a highly soluble form, 
is much less easily absorbed than when given orally. 

Besides with the urine, quinine is excreted with the feces, 
the milk, the sweat, the tears, pathologic transudates and exu- 
dates, the amniotic fluid, and the first urine of the newborn 
children of cinchonized mothers. 

Action of Quinine Upon the Malarial Parasites. — Binz, 
in 1867, was the first to assume that the effect of quinine in 
malaria was due to its action as a protoplasmic poison upon 
the organisms which he believed to be the cause of the disease. 
This conclusion was reached from a knowledge of the action 
of quinine upon infusoria. 

In 1 88 1 Laveran found that the parasites were killed by the 
addition of a I : 10,000 solution of quinine, and concluded that 
"it is because it destroys the parasites that quinine causes the 
disappearance of the manifestations of paludism." 

Since the introduction of practical staining methods numer- 
ous observations upon the action of quinine on the malarial 
parasites have been made, of which those of Craig 403 are espe- 
cially valuable and from which the following is quoted : 

"The Tertian Plasmodium (Plasmodium vivax). — The mor- 
phologic changes produced by quinine in the tertian Plasmo- 
dium, as shown by stained specimen, will first be described. 

"In order to study these it is necessary to give the drug in 
divided doses to single tertian infections, the first dose just 
before segmentation; specimens of the blood should then be 
taken and stained at intervals of every three hours for the 



342 THE STUDY OF MALARIA 

next forty-eight hours. Given just before segmentation and 
repeated at intervals of three hours, the drug acts upon the 
Plasmodia not only while free in the plasma, but also upon 
every stage of their human life cycle, and it is thus possible 
to study the morphologic changes produced by quinine in every 
stage of their development. 

"The young 'ring forms' stain very intensely after the ad- 
ministration of quinine, the protoplasm staining a much darker 
blue than normal, while the chromatin stains a dark crimson. 
Besides the increase in the intensity of the stain, the only other 
morphologic change observed is the loss of the unstained area, 
which, in normal specimens, always surrounds the chromatin. 

"In tertian plasmodia a little further advanced in develop- 
ment the staining reactions are the same as in the 'ring forms,' 
but the increased motility of the parasites is shown in the great 
number and the 'bizarre' arrangement of the pseudopodia. 
Fragmentation is observed even before the formation of pig- 
ment, some of the plasmodia at this stage being broken up 
into deeply stained portions, the chromatin lying in one of 
these portions or free near the periphery of the erythrocyte. 

"After the formation of pigment, and especially after the 
plasmodia are from one-half to three-quarters grown, the evi- 
dence of fragmentation and of extrusion of the chromatin 
from the parasite become more marked. Many of the erythro- 
cytes contained portions of deeply stained protoplasm, the chro- 
matin of the plasmodium lying free at some portion of the 
red cell. The latter is often situated at the extreme periphery 
or partly outside of the erythrocyte. 

"At this stage numerous extracellular plasmodia are seen, 
either undergoing fragmentation or hydropic degeneration. 
Many of the fragments are entirely devoid of pigment, stain- 
ing a uniform deep blue throughout, while some may be almost 
filled with pigment granules. The unstained area about the 
chromatin is always absent, nor is there any indication of an 
increase in the amount of chromatin which is so noticeable 
in the normal plasmodia at this stage. 

"While at this stage many fragmented plasmodia are usually 
observed, in some instances no evidence of this process is 



TREATMENT 343 

seen. The protoplasm stains a uniform dark blue, the pigment 
being collected, as a rule, about the periphery, while the chro- 
matin stains intensely and may be situated at any portion of 
the organism, but usually near the periphery. There is no 
unstained area surrounding the chromatin. 

"In many instances the chromatin is situated at the extreme 
periphery of the plasmodium or may lie partly or wholly out- 
side of it within the erythrocyte, thus proving that quinine 
possesses the power of causing extrusion of the chromatin, 
thus rendering the plasmodium sterile. 

"Together with the absence of the vesicular portion of the 
nucleus, as shown by the loss of the unstained area surround- 
ing the chromatin, there is but seldom, even in those organisms 
which are not undergoing fragmentation, any evidence of in- 
crease of the chromatin, and never any evidence of its division. 

"When the tertian plasmodium is nearly full grown quinine 
very often causes fragmentation, many of the fragmentated 
organisms being free from chromatin, but the characteristic 
change from the normal at this stage of growth consists in 
the fact that, although the chromatin may be present and stain 
very intensely, it has increased but little or not at all in amount, 
and division is either absent or imperfect, only two or three 
small masses being present, which lie close together near the 
periphery of the organism. In tertian plasmodia which have 
not been influenced by quinine and have reached this stage of 
development, the chromatin has always increased largely in 
amount and divided into several small clumps, which are scat- 
tered throughout the organism. The morphology of the plas- 
modia at this period of their growth indicates clearly that 
quinine prevents an increase in the amount of the chromatin, 
and either hinders division or stops it altogether. 

"At this stage the protoplasm of the organism stains deeply, 
and the pigment is collected about the periphery in blocks or 
granules, or distributed throughout the protoplasm in the form 
of fine granules or small clumps. 

"The unstained area about the chromatin is always absent. 
Those plasmodia which sporulate after being exposed to the 
action of the quinine throughout their entire cycle of develop- 



344 THE STUDY OF MALARIA 

ment present very marked morphologic evidences of the inju- 
rious effect of the drug - . While sporulation may not be entirely 
prevented, the majority of the spores are devoid of chromatin 
and are undoubtedly sterile. The segments are also decreased 
in number and may be distorted in shape, while in the seg- 
ments which show the presence of chromatin the latter is in the 
form of irregular masses, very distinct from the usual form 
as seen in normal plasmodia. Very often sporulating bodies 
are observed in which only two or three of the segments pos- 
sess chromatin ; in such segments the protoplasm stains a deep 
blue and there is no unstained area surrounding the chromatin. 

"Associated with the chromatin containing segments are 
from six to eight, or perhaps more, deeply stained segments 
containing no chromatin. 

"In the segmenting plasmodia the pigment, instead of being 
collected in a dense, compact mass, as is the rule in the normal 
tertian plasmodia, is reduced in amount and scattered in small 
clumps or granules between the segments. 

"From the morphologic changes described it is evident that 
quinine, administered in divided doses, exercises a markedly 
injurious effect upon every stage in the human life cycle of 
the tertian plasmodium, either causing the death of the organ- 
ism at some period of its development or preventing normal 
sporulation by restraining the division of the chromatin prior 
to segmentation. The death of the organism is evidenced by 
fragmentation or the extrusion of the chromatin, while the 
effect upon sporulation is shown by the limited division of 
the chromatin and the large number of segments which are 
devoid of this essential portion of the nucleus. 

"If quinine is administered in one large dose, which is not 
repeated, at any stage of the development of the tertian Plas- 
modium prior to segmentation, the changes produced are the 
same in kind as those already described, but a comparatively 
large number escape entirely or are but little injured. 

"When quinine is administered just prior to segmentation it 
does not, as has been maintained by numerous authorities, 
prevent segmentation, nor do the stained preparations show 
any distinct morphologic changes in the segmenting bodies. 



TREATMENT 345 

"The Quartan Plasmodium {Plasmodium malaria). — The 
changes produced by quinine in the quartan plasmodium, as 
shown by stained preparations, are the same as those described 
for the tertian plasmodium, and I cannot agree with Golgi 
and Antolisei that upon the adult plasmodium the drug has no 
effect. I have not been able to observe any difference, so far 
as morphologic evidence goes, in the effect of quinine upon the 
tertian and quartan plasmodia, although it is undoubtedly true 
that, because of greater resistance to the drug, a larger number 
of quartan plasmodia escape destruction at the time of sporu- 
lation. 

"The Estivo- autumnal Plasmodia {Plasmodium immacu- 
latum). — I have not been able as yet to study the effect of 
quinine upon the full-grown or segmenting estivo-autumnal 
plasmodia, but have studied many specimens containing the 
'ring forms' and the young pigmented forms. The results of 
my observations are opposed to those of Marchiafava and 
Bignami, who claim that no morphologic changes are produced 
in these plasmodia by the drug, and that the unpigmented para- 
sites do not become pigmented after its administration. I 
have repeatedly seen pigmented forms of both the tertian and 
the quotidian estivo-autumnal plasmodia develop after quinine 
had been administered for as long as three days, while the 
morphologic changes produced are similar, but not as marked 
as those observed in the tertian and quartan plasmodia. 

"In the 'ring forms,' which are most easily studied, the 
staining capacity of both the chromatin and the protoplasm is 
increased, but the unstained area surrounding the chromatin 
disappears. A large number of the 'ring forms' may appear 
normal, but careful examination will always show that numer- 
ous parasites show the loss of the unstained area and the 
'rings' are distorted in shape owing to increased ameboid 
movement. In a few instances I have observed the separation 
of the chromatin from the body of the plasmodium, thus show- 
ing that extrusion had occurred. I have never observed frag- 
mentation of the 'ring forms.' 

"The changes produced in the young pigmented estivo- 
autumnal plasmodia are similar in every respect to those occur- 



346 THE STUDY OF MALARIA 

ring in the tertian and quartan plasmodia, consisting in frag- 
mentation, loss of the unstained area surrounding the chro- 
matin, and extrusion of the chromatin." 

It is well known that the sexual forms of the malarial para- 
sites are very resistant to quinine, persisting in the blood for 
weeks and months despite the liberal use of quinine. 

While young and half-grown tertian and quartan gametes 
are sometimes destroyed by quinine, those of the estivo- 
autumnal variety are exceedingly difficult to kill. In fact, it 
has been maintained that the administration of quinine to 
patients harboring only the asexual forms favors the develop- 
ment of crescents. 

Schaudinn 134 infected anopheles mosquitoes with tertian 
gametes from the blood of his servant girl, who had been 
taking a gram of quinine three times weekly for a month. 

Gualdi and Martirano 150 arrived at the following conclusions 
with respect to the effect of quinine upon crescents : 

i. Quinine administered in a single dose of 2.50 grams or of 
1. 00 to 1.50 grams for many consecutive days is not able to 
cause the disappearance of crescents from the blood. 

2. Quinine in doses sufficient to destroy ameboid forms of 
the parasite not only do not destroy the crescents, but do not 
inhibit their development within the body of the mosquito. 

3. Quinine does not appreciably shorten the period during 
which crescents remain in the blood after the cessation of fever, 
the period which represents the contagious term of the disease. 

Macrogametes are more resistant to the effects of quinine 
than are the microgametocytes. This may possibly be due to 
the thicker protoplasmic body of the former, and explains the 
difficulty of interrupting the parthenogenetic cycle, the cycle 
of chronic or latent malaria. 

Binz observed that infusoria were stimulated to increased 
movement by quinine. The same has been noted with the 
parasites of malaria. 

According to Mannaberg, 404 a short time after the adminis- 
tration of quinine medium-sized tertian parasites are often 
observed in very active, even convulsive, movement, from 
which it appears that the parasites are at first irritated to 



TREATMENT 347 

increased movement. Bacelli 131 observed the same in quar- 
tan parasites. 

Cohen 305 believes this action of quinine to be useful in diag- 
nosis. He states that in cases of doubtful diagnosis the injec- 
tion of a quantity of the drug not sufficient to insure a definite 
freedom period will frequently cause the appearance in the 
peripheral blood of organisms recognizable as normal or atypic 
forms of the hemameba of malaria, and this has been observed 
so frequently and in so many diverse conditions that he is 
inclined to look upon its absence after, say, half a dozen injec- 
tions, varying from three da.ys to a week apart and in doses 
increasing from 0.3 to I gram, as virtually excluding malarial 
infection. He is of the opinion that in such cases the organism 
is resting in some larval form, probably in the spleen or bone- 
marrow, and that its appearance peripherally is part of a de- 
fensive, reproductive reaction to the paratoxic effect of quinine. 

That small doses of quinine are able to arouse latent malaria 
is, in the writer's opinion, unquestionable. This can only be 
explained satisfactorily by assuming that quinine stimulates 
the parthenogametes into a compensatory reproduction. 

The relation of the time when the quinine is administered 
to the temperature curve and the behavior of the parasites has 
been carefully studied by Marchiafava and Bignami, 22 the re- 
sults of whose observations may be summarized as fol- 
lows: 

1. If the quinine is administered during the crisis of an 
attack and continued during the apyrexia, which follows in the 
majority of cases, the next expected attack is inhibited or 
there is merely a slight elevation of temperature, with a slight 
sense of discomfort. In a smaller number of cases, even when 
strong doses of quinine are given during the crisis and the 
period of apyrexia, the attack is not prevented, but is delayed 
and abortive. 

2. If quinine in the usual dose is administered within the 
six hours preceding the expected attack it may have no influ- 
ence at all upon the temperature of the succeeding paroxysm. 
In other cases there is noticed a slight delay in the attack, 
which also is less severe than the preceding one, but even in 



348 THE STUDY OF MALARIA 

this case the temperature curve is the typic one of an estival 
tertian. Subsequent attacks, as a rule, do not occur. 

3. If the remedy is administered at the onset of the attack 
in the majority of cases the attack will come on in the usual 
way, and may even be grave and prolonged ; very often, how- 
ever, there are some modifications in the curve. A subsequent 
attack does not usually occur, although there may be frequent 
irregular elevations of temperature. 

4. When the quinine is given during the febrile attack be- 
ginning shortly after the onset and continuing throughout the 
course of the fever in a series of cases the characteristic curve 
of the tertian is not appreciably modified, while in another 
series there are various modifications. In a whole series of 
cases when the quinine has been given in large amount during 
the attack, there are apt to be no subsequent attacks, or on the 
following day or days there are only slight elevations of tem- 
perature. 

5. If quinine is given near the time of the crisis when the 
blood contains only young non-pigmented parasites, and if 
its administration is continued for about twelve hours, the 
parasites continue to be seen in the peripheral blood for 
nearly twenty-four hours, together with pigmented leuko- 
cytes. 

6. If quinine is given in the last hours preceding the attack, 
when the only bodies found in the blood are the pigmented 
adult parasites, or these predominate, then the parasites go 
on to their development up to fission, but the new generation, 
as a rule, does not present itself in the following attack. In 
other cases, while we do not see the generation of young para- 
sites, we have bodies belonging to the crescent group ; it would 
appear that in this case the parasites, instead of going on to 
sporulation, take the other road which leads to the formation of 
crescent forms. 

7. When the remedy is given at the beginning of the attack, 
at the time when in the blood we find fission forms, or those 
that have already become divided, the action of the remedy 
is subsequently recognized by the fact that the ameba of the 
new generation become extremely scarce, and if the quinine be 



TREATMENT 349 

continued they disappear entirely from the blood within the 
twenty-four hours. 

It is the uniform result of experience that the stage of the 
parasite most susceptible to the action of quinine is the mero- 
zoite, the spore before it has assumed the protection of the 
red cell. Hence it is desirable to have in the blood as strong 
a solution of quinine as possible at the time of sporulation, that 
the young parasites may be born into a toxic medium. 

The exact manner in which quinine destroys the parasite of 
malaria is not certain. Whether it acts as a direct poison to 
the parasite, or by stimulating phagocytosis, or by increasing 
the fluorescence of the blood, or by forming indigestible 
combinations with the blood elements has not been deter- 
mined. 

Golgi's 131 scale of susceptibility of the parasites to quinine, 
with reference to the variety of the parasite, is, i, tertian; 2, 
quartan, and, 3, estivo-autumnal ; arid, with reference to the 
stage of the parasite, 1, spores; 2, mature forms before begin- 
ning sporulation; 3, endoglobular young forms. 

Some Effects of Quinine Upon the Human Organism. 
— Quinine is one of the few drugs possessed of great thera- 
peutic power which has relatively little toxic property; never- 
theless, in exceptional instances, untoward effects result from 
its use. Reference is not made to the group of symptoms 
known as cinchonism, ringing in the ears, slight deafness, roar- 
ing, the fulness in the head, dizziness, nervousness, a bitter 
taste, and slight nausea. But manifestations of a more serious 
nature occasionally arise. 

Practitioners are very often told by patients that they cannot 
take quinine. The writer has made it a rule to disregard 
such statements and to administer quinine where indicated, 
disguised if need be, and in only two instances has he had cause 
for regret. 

One case was that of a rather nervous woman in whom 
3 grains of the bimuriate of quinine, given orally, produced 
within half an hour distressing urticaria and nervousness, and 
alarming dyspnea and depression which lasted for several 
hours. There was no lesion of the heart or other organs. This 



350 THE STUDY OF MALARIA 

same effect had several times formerly resulted from small 
doses of quinine. 

The other case was that of a woman with a mitral regurgi- 
tant murmur, who stated that every time in her life that quinine 
had been given her she thought she would die of suffocation. 
Three grains of euquinine in powder were given her, and in 
a short time she was prostrated, suffering with severe dyspnea 
and fear of death. These symptoms lasted about an hour. 

Gudden 405 observed in several patients as a result of I gram 
of quinine, headache, nausea, vomiting, a sense of burning heat, 
a chill, and elevation of temperature to 102.2° F., and pulse to 
164. The urine contained no albumin. 

Plehn 406 records a case of a woman who, a few minutes after 
taking ]/o gram of quinine, was seized with itching of the 
skin, an erythematous rash upon the neck and breast, a chill, 
and rise of fever to 102° F. After the intramuscular injection 
of 1 gram of quinine the temperature became 104° F. The 
urine was normal and the elevation of temperature lasted only 
a few hours. 

Trousseau and Pidoux 86 report the case of a patient who 
took at one dose 3 grams of quinine for the cure of asthma, 
which recurred every day at a certain hour. Four hours later 
he experienced ringing in the ears, dizziness, and terrific vomit- 
ing. Seven hours after taking the drug he was blind and deaf, 
delirious, and unable to walk on account of vertigo. He was 
vomiting constantly. These symptoms ceded spontaneously 
during the middle of the night. 

Grenier 407 cites the example of a girl of fifteen years who 
took a moderate dose of quinine for an attack of fever. A 
short time later she had nausea, vertigo, deafness, visual dis- 
turbances, swelling of the face, dyspnea, profound prostration, 
general urticaria, edema of the hands and feet, and vomiting. 
These symptoms disappeared in the course of six hours, but 
returned each time even a small dose of quinine was given, 
even though unrecognized. 

Large doses of quinine may even prove fatal. Laveran 1 
speaks of two soldiers, intending to take sulphate of soda as 
a purgative, took by mistake 12 grams each of quinine. In 



TREATMENT 35 1 

half an hour they were taken with cramping in the stomach, 
vomiting, facial pallor, dilatation of the pupils, superficial res- 
piration, chilliness ; pulse small, irregular, sometimes insensible, 
and a tendency to syncope. One of the patients recovered, the 
other died in collapse. 

Quill 408 reports the case of a patient who took y 2 ounce 
of the sulphate of quinine. Toxic symptoms appeared within 
two minutes; these were retching and vomiting, unconscious- 
ness, slow and labored respiration, a barely perceptible pulse, 
convulsions, affecting chiefly the lower extremities. Death fol- 
lowed soon. 

Numerous other cases of quinine poisoning could be cited. 
The symptoms most frequently recorded are headache, de- 
lirium, muscular weakness, staggering gait, dyspnea, collapse, 
deafness, amaurosis, psychic disturbance, cutaneous eruptions, 
hemorrhages, and fever. 

Fever caused by quinine was recognized as early as 1790 
by Hahnemann. 409 He says : "For experiment's sake, I took 
60 grains of cinchona bark twice daily for a few consecutive 
days ; my feet and hands became cold, followed by a feeling of 
malaise, palpitation of the heart, pulse hard and rapid, a feel- 
ing of apprehension, then a beating headache, flushing of the 
cheeks, thirst, and all the usual symptoms of intermittent fever. 
These symptoms lasted two to three hours each time and re- 
turned after each dose. I stopped the bark and I was 
healthy." 

Numerous cases have since been observed. F. Plehn, 5 who 
had a number of cases, believes that, while it appears more 
often in tropic than in temperate climates, it may occur in those 
who have never suffered with malaria, and occurs oftener in 
old residents than in newcomers. The fever may be preceded 
by a chill, is accompanied with other evidences of cinchonism, 
and is sometimes associated with the cutaneous manifestations 
of quinine. 

For the report of a case in this country, with an interesting 
review of the literature and a bibliography, the reader is re- 
ferred to the article of Goodman. 409 This writer believes the 



352 THE STUDY OF MALARIA 

explanation of this untoward effect of quinine to be that some 
chemic changes in the blood act on the heat-dissipating appa- 
ratus in persons who have, or have had, malaria. 

The condition is as yet too obscure to warrant any conclu- 
sions. A careful study of the blood might reveal the patho- 
genesis. . Some cases probably bear an analogy to the condi- 
tion produced by quinine in certain persons whom Koch 
designates "blackwater-fever candidates." 

Quinine in large doses is undoubtedly somewhat depressing 
to the heart, as exemplified in some of the cases recited. It 
may cause syncope, or even collapse and death. In fatal cases 
the heart is said to be arrested in diastole. 

Quinine may cause temporary psychic disturbance, even in- 
sanity and delirium. The latter occurs either in an active, 
noisy form, with loquacity and agitation, or in a quiet form, 
with stupor and depression. 

The chief digestive disorders referable to quinine are nausea, 
vomiting, anorexia, and gastric and intestinal catarrh. Gastric 
and intestinal hemorrhages have been attributed to the use 
of the drug, as well as hemorrhages from the mouth, gums, 
nose, lungs, skin, and conjunctiva. 

The cutaneous eruptions of quinine origin may be caused by 
small doses. They are most apt to follow the administration 
of the sulphate. The writer has seen persons in whom the 
sulphate had always produced annoying urticaria, take the 
bimuriate with no untoward effect. The pruritus attending 
some of these eruptions is sometimes agonizing, the patients 
declaring that the remedy is worse than the disease. 

It is said that laborers in the manufacture of quinine often 
experience pruritus of the hands and forearms, followed by 
redness and a lichenoid eruption, sometimes with swelling of 
the face and genitals. 

Urticaria is, in the experience of the writer, the most fre- 
quent of these manifestations. It may be general or quite 
local, and is sometimes attended with edema of the face and 
hands. The writer has seen only one such case in the negro 
race. 

Erythema, scarlatinal or morbilliform in appearance, is some- 



TREATMENT 353 

times observed. It may be followed by desquamation and 
prove difficult of diagnosis. 

Vesicular eruptions are but rarely seen as the result of 
quinine administration. Petechias are occasionally noted, and 
Kulz 90 has reported a case of purpura hemorrhagica referable 
to i gram of quinine. The hemorrhages proceeded from the 
stomach, intestines, mouth, nose, skin, and conjunctiva. The 
entire skin was covered with petechias from the size of a lentil 
to that of a dollar. Even the pinching between the fingers of 
a fold of skin resulted in a purpuric spot. Quantities of blood 
were vomited and purged. The temperature remained normal 
and the general condition was surprisingly little disturbed. 
Under rest, opium, diet, and tamponning of the gums the 
hemorrhages ceased upon the first day. Eight days later the 
administration of .05 gram of euquinine was followed in three 
hours by similar symptoms. Afterward an injection of quinine 
precipitated an attack of hemoglobinuria, which terminated in 
recovery. 

The pathogenesis of these skin lesions is not clearly under- 
stood, but it is probable that they are produced by some action 
of the drug upon the skin in its elimination through the sweat 
glands. 

Considering the fact that quinine is in great part eliminated 
by the urinary organs, these organs suffer but few untoward 
effects. The drug has only a slight diuretic action. Albu- 
minuria has been observed following the administration of the 
drug to malarial subjects, but whether this was due to the 
drug or to the disease is questionable. Cases of so-called 
hematuria have been reported as a result, but many of these 
cases were undoubtedly hemoglobinuria, the result of hemolysis 
rather than of local irritation. 

The role of quinine in the production of hemoglobinuria has 
been considered. 

Uterine colic may result from quinine, and the writer has 
seen several instances of metrorrhagia and menorrhagia. 

Inasmuch as abortion not infrequently occurs in the course 
of malarial fever treated with quinine, this effect is often at- 
tributed to the drug. While quinine undoubtedly strengthens 

23 



354 THE STUDY OF MALARIA 

preexisting uterine contractions, it is extremely doubtful 
whether it initiates labor pains except in a very limited number 
of cases. The writer has several times seen patients threatened 
with miscarriage whose pains were promptly quieted by the 
immediate administration of quinine, and he believes that abor- 
tion in these cases is oftener due to too little quinine than to 
too much. Pregnant women may take quinine prophylactically 
for long periods, and if they keep free from malaria they show 
no tendency to abort. 

The effect of quinine upon the eye is sometimes a matter 
of much concern. Total blindness may result, but fortunately 
this severe degree does not last long, though some constriction 
of the visual field may persist permanently. Quinine ambly- 
opia is usually accompanied by other toxic effects, being due 
ordinarily to large doses of the drug continued for several 
days. The condition is usually bilateral and attended with 
photophobia, dilated pupils, diminished pupillary reaction, color 
blindness, concentric restriction of the visual field, retinal 
anemia, with vascular constriction and atrophy of the optic 
nerve. DeSchweinitz found quinine and urea more toxic with 
reference to the eye than any other preparation he employed. 
The prognosis is usually good, normal vision being entirely 
regained in the majority of cases, but the condition may per- 
sist for months. The differentiation of this condition from 
malarial amaurosis has been considered. 

Tinnitus and a degree of deafness are common results of 
quinine. The deafness may be temporarily complete. Con- 
gestion of the malleolus, with opacity and retraction of the 
drum, are the common conditions present. 

The action of quinine on the spleen is doubtful. While 
Catani, 410 Rochfontaine, 410 Herrlich, 409 and Piorry 86 maintain 
that it causes a contraction, even of the healthy organ, their 
results could not be confirmed by Valleix and Briquet. 86 

The behavior of the leukocytes under the influence of quinine 
is disputed. Vincent and Bastianelli 86 observed that the ad- 
ministration of quinine caused an increase in the number of 
mononuclear leukocytes. Billet 86 noted that within three to five 
hours after administration there occurred a diminution of the 



TREATMENT 355 

leukocytes, and in ten or twelve hours a mononuclear increase, 
even greater than the average for untreated malaria. 

Binz maintained that quinine interfered with the movements 
of the leukocytes and with diapedesis, but Hayem was unable 
to verify these observations. 

Marchiafava and Bignami 162 observed a remarkable develop- 
ment in the phagocyte phenomena after the administration 
of the salts of quinine, but believed that it was not due to an 
increase in the phagocyte energy brought about by the drug, 
but to the greater quantity of necrotic forms, and of free 
pigment, which is diffused in the blood in consequence of the 
direct action of the remedy on the parasites, the phagocytes 
removing the dead forms which render the blood impure. All 
that these writers could say with certainty was, that the salts 
of quinine do not hinder the phagocyte activity of the white 
blood corpuscles, nor is their mobility modified. 

Disselhorst and others 233 proved by experiments upon frogs 
that the motility and the phagocyte function of the leukocytes 
is unimpaired by quinine. Mannaberg 404 considered that the 
phagocytes in the internal organs have their functions rather 
weakened than stimulated by quinine. 

Contra-indications to the Use of Quinine. — The mere state- 
ment of the patient that he is unable to take quinine should 
constitute no bar to the use of the specific. The history of the 
invariable sequence of very severe skin manifestations should 
perhaps lead the physician to employ one of the substitutes for 
quinine. 

Cardiac depression and dyspnea are a decided contra-indica- 
tion to the administration of the drug. 

The treatment of malaria complicating pregnancy is essen- 
tially the same as under other conditions. A fear, probably 
more fancied than real, of the oxytocic properties of quinine is 
widely prevalent, but of the dilemma, malaria or quinine, the 
latter is certainly the shorter horn. The pregnant patient runs 
far less risk of abortion with rational quinine treatment than 
without. Malaria during pregnancy is notoriously stubborn, 
and, while the attack should be treated with the smallest doses 
necessary to effect a prompt cure, systematic and prolonged 



356 THE STUDY OF MALARIA 

quinine prophylaxis is necessary to prevent recurrences. If 
labor pains have begun opium should be administered with the 
quinine. 

The history of hemoglobinuric fever is no contra-indication 
to the use of quinine. While the administration of the drug is 
sometimes the occasion of an outbreak of blackwater fever, the 
latter is generally due to too little quinine rather than to too 
much. Nor is it advisable to restrict the size of the dose 
unnecessarily through fear of an attack, since it has been shown 
that the amount of quinine is of little importance in the eti- 
ology, very small quantities being as prone to occasion the 
attack as moderate amounts. 

Choice of Preparation. — This is influenced by the age of 
the patient, the mode of administration, the severity of the 
attack, and other factors. 

The sulphate, on account of its cheapness and ease with 
which it is obtained, is widely employed. The writer, however, 
now rarely employs it, and then only in suspension in syrup of 
yerba santa for children. It is probable that it gives rise to 
more gastro-intestinal and nervous disturbances than any other 
salt of quinine, and it is these manifestations produced, as a 
rule, by this salt which cause so many persons to say to the 
physician that they cannot take quinine. 

The bisulphate, the hydrobromide or bromide, and the hydro- 
chloride are useful preparations, being easily dissolved and 
readily absorbed. 

The bimuriate, or acid hydrochloride, or bihydrochlorate is 
the most valuable salt of quinine. Its great solubility adapts it 
for solution to be given by mouth, by rectum, intramuscularly, 
or intravenously. 

Euquinine, or quinine ethyl carbonate, has been thoroughly 
tried and has given satisfactory results in the writer's hands. 
Being practically tasteless, it is easily administered, either in 
powder or suspended in a neutral syrup, to children. An acid 
with the drug or immediately following develops a bitter taste. 
The objections to the preparation are its expense and the fact 
that it is patented. 

The tannate of quinine, on account of its small proportion of 



TREATMENT 357 

alkaloid and slight solubility, has been until recently only rarely 
employed in the therapy of malaria. The Italian Government, 
in an effort to supply a tasteless salt of quinine for children, 
has been dispensing tannate of quinine in the form of choco- 
late confections. A commission of members of the Superior 
Council of Health, appointed to investigate the results obtained 
by this method of administration, reported adversely. They 
concluded that the tannate of quinine is one of the most insol- 
uble preparations of quinine, and that it is weakly and slowly 
acted upon by the digestive fluids ; that the fat of the cocoa 
retards the action of the digestive fluids upon the quinine and 
causes it to deteriorate under the influence of the air. This 
report was the occasion of a unanimous remonstrance by 
numerous physicians who obtained excellent results from the 
use of the tannate. 

The experience of the writer with this salt, together with 
the reports of the Italian physicians, leads to the following 
conclusions : 

i. The tannate of quinine is almost completely absorbed 
from the alimentary tract. 

2. It is more slowly absorbed and more slowly eliminated 
than the other salts of quinine, and remains in the system 
longer. 

3. A small quantity only of the salt is acted upon by the gas- 
tric juice, but is largely absorbed from the bowel after contact 
with the bile and pancreatic juice. 

4. It is not absorbed when injected into the rectum. 

5. It is better tolerated by the stomach, intestines, and ner- 
vous system than the sulphate. 

6. The clinical results with the tannate of quinine are en- 
tirely satisfactory. 

7. Being nearly tasteless, it is especially adapted to the treat- 
ment of malaria in children. 

8. It has a good effect upon diarrhea and dysentery compli- 
cating malaria. 

9. It is several times less expensive than any other tasteless 
preparation of quinine. 

Methods of Administration of Quinine. — Administration 



358 THE STUDY OF MALARIA 

by the Mouth. — In simple cases of malaria, administration of 
quinine by the mouth is the rule ; by other methods the excep- 
tion. It is probable that ninety-nine-one-hundredths of the 
quinine consumed is given by the oral route. 

There are those, not objecting to the taste of quinine, who 
will take it in the powdered form; in fact, it is a common 
method among the Southern negroes to lick it from the palm 
of the hand. The taste is, however, so repulsive to most per- 
sons that, with the exception of the tannate and euquinine, it 
must be given in some other form. 

The same objection applies to giving the drug in solution, 
though this is unquestionably the most reliable form in which 
to give it by the mouth, but for obvious reasons it cannot be 
so extensively employed in this manner in private practice. 
The solution is more quickly and completely absorbed. The 
bimuriate and the bisulphate are the salts most suitable for 
solution, but if neither of these is at hand the sulphate may be 
employed by adding a drop of dilute hydrochloric or sulphuric 
acid for each grain of the quinine. 

The most efficient vehicle for disguising the taste of the 
sulphate of quinine is the syrup of yerba santa. Two grains 
of quinine to the dram of the syrup is the suitable proportion. 
Syrup of chocolate, fluidextract of licorice, ginger, coffee, 
milk, honey, olive oil, and other media have been recommended, 
but are far from satisfactory. Acid fruit juices and syrups 
usually enhance the bitter taste. 

Where prejudice against quinine makes it necessary to dis- 
guise the appearance of the drug, this may be accomplished 
effectively by adding a small quantity of charcoal, turmeric, 
or methylene-blue to the bimuriate, bisulphate, or other salt. 

Pills and tablets are convenient to administer and not un- 
pleasant to take, but cannot be relied upon. The coating often 
becomes so hard as to make solution difficult or impossible. 
The writer has several times seen quinine given in this form 
pass from the bowel wholly unaffected. Pills and tablets 
should not be given when capsules can be obtained. Capsules, 
when fresh, are easily dissolved. If there is any doubt as 
to their quality they may be punctured several times in each 



TREATMENT 359 

end with a pin, or may be followed by a few drops of a dilute 
mineral acid. 

In the absence of capsules quinine has been rolled in a little 
ball with cigarette paper. Absorption is extremely slow and 
uncertain, and this method should not be resorted to. 

The tannate of quinine has been compounded with the choco- 
late confection for administration to children, and in this form, 
if reliably made, is readily taken, and in sufficient dose is 
efficient. 

Hypodermic Method. — Quinine was used hypodermically at 
least as early as 1863, when Bourdon 289 employed the sulphate 
dissolved in water with tartaric acid. The same year Moore 411 
recommended the use of 30 grains of the sulphate of quinine 
dissolved in J / 2 ounce of water by means of 8 or 10 drops 
of dilute sulphuric acid, from 1 to 1^ drams of this solu- 
tion to be used at a dose. Bad results were common. 
Arnould, 412 in 1867, reported in 95 cases thus injected 2 
indurated nodes, 4 eschars, and 15 abscesses. In 1888 Beur- 
mann and Villejean 412 introduced for hypodermic use the bi- 
muriate in the following formula, which is still widely em- 
ployed : 

Quinine bimuriate 5 gm. ; 

Distilled water to 10 cc. 

Kobner 86 recommends : 

Quinine hydrochlorate 5-1 gm. ; 

Glycerine, \ 

Distilled water J aa 2 gm. 

Grimmaux : 86 

Quinine hydrochlorico-sulphate 5 gm. ; 

Aqua dest 6 cc. 

Klein : 96 

Quinine hydrobromate 2 gm. ; 

Sulphuric ether 12 cc. ; 

Alcohol q. s. 20 cc. 

Triulzi 86 added antipyrine to promote solution and diminish 

pain: 

Quinine muriate 3 gm. ; 

Antipyrine 2 gm. ; 

Aqua 6 cc. 



360 THE STUDY OF MALARIA 



Vincent and Burot 



.96 



Quinine muriate 3 gm. ; 

Analgesin 2 gm. ; 

Aqua 6 cc. 



Gaglio 



.86 



Quinine hydrochlorate 3 gm. ; 

Urethane 3 gm. ; 

Aqua 5 cc. 

The addition of cocaine has been recommended also to lessen 
the pain. 

The most suitable salt of quinine for injection is unques- 
tionably the bimuriate. The tablets of bimuriate of quinine 
and urea are convenient and insure accurate dosage. The 3- 
grain tablets contain approximately 2^4 grains of the quinine 
salt. 

The advantages of giving quinine by the needle in pernicious 
malaria are obviously being able to administer it to patients 
unable to swallow or to retain it, and the certainty and prompt- 
ness of absorption. Nevertheless, these great benefits are some- 
what discounted by the bad results which sometimes appear. 
Formerly tetanus was to be feared. Bartholow 413 mentions 
several such cases reported from New Orleans and 2 occurring 
in one regiment of the British Indian Army. Vincent, 414 in a 
late report, recalls the numerous cases following the sub- 
cutaneous use of quinine. McCampbell 415 speaks of a fatal 
case of tetanus shortly following a hypodermic injection of 
the hydrochlorate of quinine, though the experiments of this 
writer fail to corroborate those of Vincent to the effect that 
the injection of quinine favors the development of the tetanus 
bacillus. In the late French campaign in Madagascar 6 cases 
of tetanus subsequent to hypodermics of quinine came under 
observation. But there are other consequences which, while 
not so deadly, are more commonly met. Nodules, necrosis, 
sloughing, and abscess formation are referred to. Plehn 171 
and Bliimchen 416 have frequently seen necroses and abscesses 
result from hypodermics of quinine. Thayer 98 says there is 
always danger of subsequent abscess or necrosis. Laveran 1 
states that injections made into the skin often give rise to 



TREATMENT 36 1 

eschars. Manson 417 has often seen induration, if not abscess, 
follow the hypodermic injection of quinine conducted in the 
ordinary way. Bonnette, 412 Mauviez 412 and LeDantec 226 say 
that, in spite of the greatest aseptic precautions, eschars and 
abscesses will sometimes result. Craig 418 has observed ab- 
scesses in about 20 per cent, of the cases, and often had nodular 
elevations at the seat of puncture which persisted for some time. 
Gros, 419 Shoemaker, 420 and Tyson 421 have abandoned the 
method on account of the frequency of inflammation and ab- 
scess formation. 

These results, however, should not prevent the use of quinine 
injections in the treatment of pernicious malaria, as such 
effects are, in a great measure, preventable. To this end there 
are three measures of importance : First, asepsis ; second, di- 
lute solutions, and, third, deep injections. 

The first is at the present day probably the least often 
neglected, as most physicians realize the importance of steriliza- 
tion, and a spoonful of water and a few matches are sufficient 
to effect it on the part of the solution and needle, and soap 
and water are almost omnipresent. 

The necessity of employing a dilute solution has been all 
but ignored. Nearly all writers on the subject lay great stress 
on the need of asepsis, but with few exceptions even mention 
the evils of too concentrated solutions. Strong solutions of 
quinine injected into the tissues cause a wall of necrosis around 
the solution, preventing absorption and paralyzing phago- 
cytosis, resulting, even if the solution is sterile, in nodes or 
ugly chemic sloughs. It is in all probability this chemic irrita- 
tion of the cells which allows of bacterial infection following 
the injections of solutions not properly sterilized, and, no 
matter how sterile the solution, if too concentrated, a nodule 
or chemic slough is apt to result. Witness the frequency with 
which unsterilized solutions of morphine and other drugs are 
given without the slightest bad consequence. 

For injection purposes the following formula is most suit- 
able: 

Quinine bimuriate 1 gm. (gr. xv) ; 

Water 10 cc. (dr. iiss) . 



362 THE STUDY OF MALARIA 

As much of this as needed may be injected in one or several 
locations. 

The solutions should not be injected hypodermically, but 
intramuscularly, since in the latter location the injection is 
more certainly absorbed, is less apt to cause induration and 
abscess, and is less painful. In some cases of pernicious 
malaria the superficial circulation is very poor, absorption cor- 
respondingly inadequate, and necrosis almost inevitable if the 
quinine is not deeply injected. In a case of algid malaria in 
my practice where the quinine was given hypodermically the 
site of injection began to turn blue within ten minutes and 
was almost black within two hours. 

The initial dose should ordinarily be 15 grains. Afterward 
from 5 to 10 grains should be injected every six or eight hours 
as long as the symptoms demand it. For children under 
five years the first dose may be 1^ grains for each year of 
age. The statement of Homem, 157 that in the administration 
of quinine in pernicious malaria it is best rather to sin by prod- 
igality than by parsimony, is open to question. While there 
are few drugs so potent as quinine having so few toxic effects, 
bad results do sometimes follow excessive doses. Schellong 92 
noticed that large doses added to the insult to the nervous 
system and had a depressing effect on the heart. As Plehn 5 
expresses it, there is a universal tendency to attribute all bad 
phenomena to the disease and all favorable ones to the remedy. 
However, after using in 5 cases 5 to 6 grams in divided doses, 
repeated at short intervals during the height of fever, this 
accurate observer noted considerable depression of the heart, 
nervous system, and general condition of the patients. 

Most of the continental writers recommend the Pravaz or 
Luer syringes, with platin-iridium needles, but the ordinary 
antitoxin syringe, as used by Sutherland 168 for this purpose, 
answers as well. A soft-rubber tubing connection between the 
needle and the nipple of the syringe is advantageous, as it may 
prevent the breaking of a needle in a struggling patient. One 
of these syringes, a small sterilizing pan, and alcohol lamp do 
not occupy much space, and, being almost indispensable in these 
cases, should be easily accessible during the malarial season to 



TREATMENT 363 

the physician in a malarial locality, who often sees these cases 
miles from his office, when time is a matter of life and death. 
The ordinary hypodermic syringe may be used in an emer- 
gency, but to use a sufficient quantity of a properly diluted 
solution a number of injections have to be made. 

The best location for injection is in the gluteal region well 
above the ischial tuberosities, though the interscapular region 
is often chosen. 

The technic of intramuscular injections of quinine may be 
summarized in these precautions : Have the solution freshly 
made, thorough, dilute, and sterile; render the syringe and 
the injection site aseptic ; insert the needle into muscular tissue, 
and avoid breaking the needle. 

Intravenous Method. — In 1890 Bacelli 422 introduced the in- 
travenous administration of quinine in the treatment of perni- 
cious malaria, claiming thereby to have reduced the mortality 
from 1 7 to 6 per cent. The following formula was used : 

Quinine hydrochlorate 1.00 gm. ; 

Sodium chloride 75 gm. ; 

Distilled water 10.00 cc. 

The arm is bound above the elbow in order to distend the 
veins of the forearm, into one of which the needle is intro- 
duced in the direction of the blood current, and the solution 
injected very slowly after removing the constriction. The 
puncture should be covered with a sterile dressing. The solu- 
tion should be warm and sterile, and care should be taken 
that no air is injected. If swelling occurs at site of the injec- 
tion it is evident that the vein has not been entered. It is said 
that 1 gram of quinine thus injected produces a solution in the 
blood of 1 : 5,000, which is the strength deemed necessary by 
Binz to destroy protozoa. Rogers 44 thinks well of this method, 
and has abandoned in favor of it the subcutaneous route. How- 
ever, it probably has no advantages over the intramuscular 
administration. Moreover, it is not infrequently almost impos- 
sible to locate the veins, especially in young negroes. 

Hypodermoclysis. — Quinine dissolved in normal salt solution 
given by hypodermoclysis has been recommended by Grail 256 



364 THE STUDY OF MALARIA 

and others. From 10 to 30 grains of the bimuriate are dis- 
solved in a pint of normal salt solution, and as much as desired 
is injected into the loose subcutaneous tissue. It is extolled 
especially by Glatard 86 in the treatment of children suffering 
with pernicious malaria. This method is probably not adapted 
to the treatment of algid malaria on account of the deficient 
superficial circulation. Besides, the necessary apparatus is fre- 
quently wanting. 

Gutierrez 423 had success with injections of quinine directly 
into the spleen, but such a dangerous procedure is entirely 
unjustifiable. Fleury, 424 acting upon the theory that the nearer 
the spleen the quinine is injected the better the result, injected 
deeply into the structures below the ribs in the midaxillary line 
upon the left side. His results do not appear to have excelled 
those following injections in other sites. 

Jousset 159 treated pernicious malaria with injections of 
quinine into the trachea by inserting the needle immediately 
below the cricoid cartilage and injecting a 10 per cent, solution 
drop by drop. 

Le Dantec 226 suggests that in cases of tetanic pernicious 
malaria the subarachnoid injections of quinine, after the 
method of Jaboulay, might prove efficacious. So far as known, 
this method has not been tried in this condition. 

Rectal Administration. — This method, though uncertain, is 
of value where quinine cannot be retained by the stomach, and 
there are objections to the intramuscular injection, especially 
in children. It may also be used as an adjuvant to the intra- 
muscular or intravenous injection in pernicious cases. A 
soluble salt should be used, preferably the bimuriate. The 
water should be about the temperature of the body, and should 
not exceed a few ounces in quantity. Two or three times as 
much quinine should be given by the rectum as by the mouth, 
and the injection should be made high into the bowel. Ten 
or 15 drops of tincture of opium should be added to prevent 
tenesmus and aid retention. Antipyrine has been recommended 
by some, but should be used with care where there is depres- 
sion. A cleansing injection should be given first if the patient 
is conscious. 



TREATMENT 365 

The writer has had no experience with quinine given in 
rectal suppositories, but these are highly recommended by Shoe- 
maker. 420 Five or 10 grains should be contained in each sup- 
pository, in which may also be included a small quantity of the 
extract of belladonna to facilitate retention. 

Epidermic Administration. — The use of quinine mixed with 
fats and oils and rubbed into the skin is not to be relied upon, 
since little, if any, quinine is absorbed by the skin. 

Time of Administration and Dose. — With reference to the 
time when the drug is given, there are three chief modes of 
giving quinine : 

(1) The method of Torti, a single dose before the parox- 
ysm; (2) the method of Sydenham, a single dose in the decline 
of the paroxysm, and (3) the method of fractional doses. 

The first two methods are adapted only to the benign infec- 
tions. 

The efficacy of the method of Torti rests upon the fact that 
the parasites are most susceptible to the action of quinine imme- 
diately after sporulation, while free, before having entered the 
red cells. It presupposes an accurate knowledge of the hour 
at which the next paroxysm will occur, based obviously upon a 
definite history .of repeated paroxysms, a temperature chart, 
or blood examinations sufficiently accurate to determine not 
only the type of the organism, but its exact stage. It is evident 
that in private practice, in the patient seen in the first access, 
the prediction of the next paroxysm must usually depend upon 
the results of the examination of the blood, and that this must 
be repeated if the stage is not recognized at the first examina- 
tion. Unless this can be done quinine should not be admin- 
istered in this way, for, even if the type of malaria present is 
known, there are two conditions which may render the single 
dose futile: first, anticipation of the paroxysm; second, a 
multiple infection. Even where the blood is carefully ex- 
amined, it may happen, in double infections, that only one 
group can be detected in the peripheral blood. 

By this method, also known as the Roman method, the 
quinine is given in a single dose of about 15 grains from four 
to six hours before the next succeeding paroxysm. This 



366 THE STUDY OF MALARIA 

paroxysm is not prevented ; in fact, it may be entirely unmodi- 
fied; but such a dose, properly timed, usually secures apyrexia 
subsequently for several days. 

In double tertian infections a single dose given in this way 
may change the quotidian paroxysms into tertian, and if re- 
peated, in multiple tertian and quartan infections, constitutes 
a sort of fractional sterilization of the blood. 

The method of Sydenham, the English method, consists of 
a single dose, averaging 15 grains, given in the sweating stage 
or the decline of the paroxysm. This dose usually prevents 
succeeding paroxysms; if one should occur it is usually abor- 
tive. 

This method requires less knowledge of the exact nature of 
the infection and of the stage of development than the former 
method, hence it may be more effectively applied by the busy 
practitioner. What experience the writer has had with it has 
been satisfactory. 

The third method, that of small doses at frequent intervals, 
has numerous advantages over the one-dose methods. 

1. Quinine given in this way is better borne by the digestive 
and nervous systems. 

2. The loss of one dose by vomiting or failure of absorption 
is not of so much importance. 

3. The method is adapted to tertian, quartan, or estivo- 
autumnal infections; this is important, for sometimes these 
cannot be differentiated clinically. 

4. It is adapted especially to estivo-autumnal infections 
where sporulation is not so nearly synchronous. 

5. The time of administration is not dependent on parasitic 
findings or definite stages, both of which may be obscure where 
the patient has previously taken quinine. 

6. An experience in many hundreds of cases has proved its 
value. 

The writer gives quinine in this way almost exclusively. 
The average dose is a grain an hour, given usually 2 grains 
every two hours, 3 grains every three hours, or 4 grains every 
four hours day and night. It is especially important that the 
drug be given during the night, since thus only may the 



TREATMENT 367 

blood be charged during the day, when sporulation usually 
occurs. 

It is not necessary to defer or discontinue the use of quinine 
on account of fever, as is believed by some. More than four- 
score years ago Maillot showed that to withhold the drug for 
this reason was not only useless, but dangerous. 

Cinchonism is no guide to the quantity to be given ; it is not 
the patient toward which the quinine is directed, but the para- 
sites. 

The specific should not be discontinued as soon as the tem- 
perature is normal, but should be kept up for at least two 
days longer in the quantity employed during the fever. There- 
after about 15 grains on two successive days of each week 
should be given for at least two or three months to prevent 
relapse, even though the patient leave the malarial locality. 
A few days' treatment with quinine no more cures malaria 
than does a few weeks' rubbing with mercury cure syphilis. 

Hygienic and Symptomatic Treatment. — Rest is impor- 
tant in the treatment of malaria not only during the stage of 
active symptoms, but during convalescence. Exercise may 
counteract the benefits of quinine; it is not uncommon to see 
cases yield after confinement to bed which had previously re- 
sisted quinine. A relapse may be provoked by a too-early 
resumption of duty. Rest is especially important in the treat- 
ment of estivo-autumnal infections. 

Buttermilk is one of the most acceptable and easily retained 
articles of diet. Sweet milk, meat broths, vegetable soups, 
fruit juices with egg albumen, soft-boiled eggs, and toast are 
usually allowable. Where there is much gastric disturbance 
food had better be withheld temporarily. 

The room and bed should be screened; in this way only 
can other members of the household be satisfactorily protected. 
The room should be thoroughly ventilated and the patient 
protected from draughts. 

It is customary to begin the medical treatment with a purge. 
Calomel is the drug most easily administered and retained. 
The drug need not exceed 5 or 6 grains, and should be followed 
by a saline. The quinine should not be delayed for the action 



368 THE STUDY OF MALARIA 

of the purgative. As has been said, "cases originally violent 
almost invariably die while preparing for the quinine, and those 
of moderate severity become worse under the preparation."™ 
Calomel has been frightfully abused in most malarial coun- 
tries. It was formerly the universal practice to give the drug 
until the gums were "touched" and the teeth irreparably dam- 
aged. It was more the abuse of calomel than of any other 
drug that led Oliver Wendell Holmes 425 to declare that, ex- 
cepting a few drugs, "if the whole materia medica, as now 
used, could be sunk to the bottom of the sea it would be all 
the better for mankind — and all the worse for the fishes." 

During the cold stage blankets, hot drinks, and the external 
application of heat are indicated. Atropine hypodermically is 
useful, and morphine is indicated in some cases. 

In the hot stage, if the temperature runs high, cold applica- 
tions to the head, tepid sponging, and cold rectal injections 
may be used. The coal-tar antipyretics are not often indicated. 
Cold drinks may be given. . 

For the headache cold applications, codeine, and acetanilid, 
or chloral and bromide of soda are useful, and, if the pain 
demands it, morphine need not be withheld. If nervousness 
is marked the monobromated camphor should be administered 
with the quinine in capsules, or the bromide of soda, in solu- 
tion, with each dose of the specific. 

For vomiting, if intense and not relieved by the application 
of a mustard plaster to the epigastrium, morphine should be 
employed subcutaneously. 

Chronic Malaria. — In the treatment of chronic malaria two 
parasitic cycles have to be combated, the schizogonic and the 
parthenogenetic. The treatment of the asexual cycle of para- 
sitic evolution in chronic malaria is that of acute malaria. 

The tendency to relapse at multiples of approximately seven 
days has long been recognized, these periods being known as 
the septenary periods. It is now known that these relapses 
depend upon the sporulation of the parthenogametes, a cycle 
difficult to interrupt except during the stage of free spores. 

After successively meeting the active symptoms by quinine, 
administered as above outlined, the prevention of a relapse is 



TREATMENT 369 

to be accomplished by giving 15 grains of quinine every sixth 
and seventh days for a period of not less than three months. 
The administration of a valuable salt of quinine in this manner 
has rarely failed, in the writer's experience, to cure the most 
obstinate case of chronic malaria. The quinine is usually given 
in 3-grain doses every three hours until five are taken. 

The hygienic treatment is even of greater importance in 
the management of chronic malaria than in acute. Many 
secondary factors may arouse latent malaria, and these, which 
have been mentioned in the section on Etiology, should be 
assiduously avoided. 

Cachexia. — Nothing is more discouraging to the physician 
than the treatment of cachetics in whom the poor hygienic con- 
ditions cannot be corrected, which is not rarely the case. The 
two chief principles involved in the treatment of cachexia are, 
first, the prevention of active outbreaks of malaria, and, sec- 
ond, the improvement of the general condition of the patient 
by appropriate hygiene. 

Quinine is most effectively given upon two successive days 
in each week, as described. This alone, however, will rarely 
effect a cure except in the mildest cases. 

Where it is practicable a complete change of climate should 
be advised. Without this very little can be accomplished for 
cases of severe degree. A wholesome, nutritious, and digest- 
ible diet should be prescribed. The digestion is often impaired 
and stomachic tonics may be indicated. Exposure to inclement 
weather must be avoided on account of the dangers of pneu- 
monia. Occupations which subject the cachectic to violent 
exertion or to bodily harm should be interdicted for fear of 
rupture of the spleen. Regular hours must be kept and con- 
stipation overcome. 

Of drugs other than quinine, arsenic has the best reputation. 
It should be given in rather large doses of the arsenous acid 
or Fowler's or Donovan's solutions. Atoxyl has recently been 
introduced into the treatment of malarial cachexia. It is 
employed hypodermically, one-third grain being a moderate 
dose. The writer's limited experience with this method has 
been rather favorable than otherwise. The possibility of 

24 



37° THE STUDY OF MALARIA 

amaurosis as a toxic result of atoxyl should be borne in 
mind. 

Iron is nearly always indicated; the organic preparations of 
iron and manganese are usually well borne by the stomach. 
The pill of Blaud's mass, 2^ grains; atoxyl, one-third grain, 
may be tried, or the classic antimalarial pill of iron, quinine, 
arsenic, and strychnine. 

Injections of medicaments directly into the spleen, as some- 
times advised, are unjustifiable. 

Counter-irritation over the splenic area may aid in the re- 
duction of the enlarged spleen. The best agent is the ointment 
of the red iodide of mercury. A piece the size of a pea or 
larger should be thoroughly rubbed in, the splenic region being 
bared to the sun's rays or to the heat of a fire. This should 
be repeated daily until the skin becomes so irritated as to 
make friction painful, when it should be discontinued, to be 
resumed again when the condition of the skin will permit. 
Iodine, turpentine, mustard, firing with the actual cautery, 
and other counter-irritants have been recommended. 

Hydrotherapeutics and electricity have not given general 
satisfaction. Their use is sometimes followed by an active 
outburst of malaria. 

While the .r-rays have a destructive effect upon certain 
protozoa, they do not appear to have such action upon the 
parasites of malaria within the circulation. Demarchi, 426 as 
a result of his experiments, is convinced that, while these rays 
are useless against the infection itself, they appear to have 
a beneficial effect upon the enlarged spleen when the parasites 
have disappeared spontaneously or as the result of medication. 

Splenectomy may be performed in very anemic patients with 
large, painful spleens, especially if freely movable, in whom a 
change of climate is impossible and therapeutic measures have 
failed. The writer had the opportunity of treating an obsti- 
nate case of estivo-autumnal malaria in an adult female who 
had had, several years previously, the spleen removed on ac- 
count of malarial cachexia. Hemoglobin percentage was only 
slightly affected by the attack, and convalescence was rapid. 

Brachio 427 has recently suggested a unique method of treat- 



TREATMENT 37 1 

ment of splenomegaly. He had observed that in patients with 
splenic enlargements who suffered suppurative complications, 
as mastoiditis, empyema, cancrum oris, etc., the spleen rapidly 
diminished in size. At the same time a leukocytosis was pro- 
duced where these cells had previously been diminished, and 
to this phenomenon he attributed the improvement. In order 
to produce leukocytosis this writer injected subcutaneously 
5 minims of turpentine in the splenic region, which resulted 
in abscess formation and a consequent increase in the number 
of leukocytes. Nearly 20 cases were treated in this manner 
with the most encouraging results. While in cases with very 
large spleens it was necessary to repeat the injection, in only 
1 case was the third injection required. 

Treatment of Malaria in Children. — In the treatment of 
malaria in children it is the practice of the writer to administer 
the quinine at short intervals every two or three hours. 

While children bear quinine in relatively larger doses than 
adults, the size of the dose should be regulated by the severity 
of the attack and the age of the patient. In average cases 
children from one-half to two years of age may be given 
from y 2 to 1 grain of quinine every three hours, from three 
to five years from 1 to 2 grains, and from six to ten years 
from 2 to 2 J / 2 grains. These quantities may be increased in 
severe attacks. 

The drug is ordinarily given by the mouth. Where capsules 
cannot be used, recourse must be had to a tasteless preparation 
or to a disguising vehicle. Euquinine and the tannate of 
quinine are the best of the tasteless preparations. The former 
must be given in slightly larger doses, the latter up to double 
the doses indicated above. The most efficient liquid for dis- 
guising the taste of the sulphate of quinine is the syrup of 
yerba santa, at least 1 dram of which should be given for 
each 2 grains of the quinine. In cases with pernicious symp- 
toms the drug should, of course, be injected intramuscularly. 
Rectal administration of a solution or suppository may be 
employed to supplement other modes. The buttocks should 
be pressed together for half an hour after insertion to aid 
retention. 



372 THE STUDY OF MALARIA 

Calomel, mercury with chalk, and castor oil are efficient 
purgatives in the treatment of malaria in children. 

Treatment of Complications. — When malaria is compli- 
cated with other diseases each should receive appropriate treat- 
ment. The malaria should be promptly treated as under ordi- 
nary circumstances. Only a few complications need special 
consideration. 

For rupture of the spleen immediate laparotomy should be 
performed. With early operation over half recover, without 
operation the mortality is nearly ioo per cent. 

Abscess of the spleen is a surgical condition. The choice 
of operation between splenectomy and splenotomy must be 
based upon individual conditions. Two cases reported by 
Bell* 28 and by Goltman 429 recovered after operation. 

In the treatment of quinine amaurosis the quinine must, of 
course, be discontinued. Nitrite of amyl and nitroglycerine, 
with tonics, are recommended. 

Substitutes for Quinine. — In the treatment of malaria 
there is no other drug that can compare in efficacy to the salts 
of quinine ; nevertheless, in rare instances, it becomes necessary 
on account of idiosyncrasy to resort to the use of other reme- 
dial agents. 

Of the newer preparations of quinine, euquinine, saloquinine, 
aristochin, etc., while purported to be free from the toxic 
properties of the official salts, the writer has seen I case in 
which euquinine caused distressing dyspnea, and another case 
in which this preparation caused violent urticaria. Euqui- 
nine is probably the most valuable of these preparations. 

The alkaloids of cinchona, other than quinine, are now but 
rarely employed, and opinions vary widely as to their merits. 
Cinchonidine is probably the most useful of these alkaloids. 
It must be given in doses about twice as large as of quinine. 
These alkaloids, especially cinchonine and quinidine, are more 
toxic than quinine, producing nervous and gastric disorder 
and, in toxic doses, convulsions. 

In order to determine the value of these alkaloids in the 
treatment of malaria the English Government, in India, in 
1866, appointed a commission to investigate the subject. 161 



TREATMENT 373 

410 patients were treated with cinchonine, of which 400 were cured 
350 patients were treated with cinchonidine, of which 346 were cured 
375 patients were treated with quinidine, of which 365 were cured 

These results are, however, much better than those obtained 
by other observers. 

Good results have been obtained with Warburg's tincture. 
It is claimed that quinine may be given in this form when not 
tolerated otherwise. The liquid contains, among- its many in- 
gredients, about 10 grains of quinine to the ounce, and the 
dose is y 2 ounce repeated in two to four hours. It is prob- 
able that as good effects can be obtained by quinine alone 
in solution as with this unpalatable and unscientific conglomera- 
tion of "quinine concealed in a farrago of inert substances for 
purposes of mystification." Its composition was for a long 
time a secret. 

M ethylene-blue was introduced into the treatment of malaria 
by Guttmann and Ehrlich 430 in 1891. 

In the writer's experience this is the best substitute for the 
derivatives of Peruvian bark. While it does not compare 
favorably with quinine, requiring a longer time to effect a 
cure, and failing altogether in not a few instances, it seems to 
possess some specific action upon the parasites of malaria, 
and is the most valuable drug where the cinchona preparations 
are absolutely contra-indicated. Wood 431 collected from the 
literature 425 cases of malaria treated with methylene-blue 
with 362 cures. De Blasi 432 tried it in 100 cases with 62 cures. 
Ruge 158 considers methylene-blue as efficacious as quinine 
against quartan fever, or even more so under some circum- 
stances. Koch 33 had good results in the cases in which he 
tried the remedy, and commends its use in cases where quinine 
cannot be taken. Ziemann, 48 F. Plehn, 5 Laveran, 1 and others 
have, however, had poor results with the use of methylene- 
blue. 

Only the purest preparation should be employed for medici- 
nal purposes, otherwise untoward results may follow. 

The dose is from i}4 to 3 grains given every three hours 
until from 7^2 to 15 grains have been given in twenty- four 
hours. The drug may be continued in this manner for several 



374 THE STUDY OF MALARIA 

days. Ruge 158 has given as much as 15 grains daily for four 
weeks without bad results. It is best given in capsules. Kunst 90 
injected subcutaneously 5 cc. of a 5 per cent, solution ; in some 
cases he gave even as much as 1 gram in this manner. In the 
latter cases the patients became greenish-blue all over, the 
injection site remained painful for ten days and became par- 
tially gangrenous. 

It is believed by some observers that methylene-blue has 
more decided curative effect upon chronic than upon acute 
malaria. It is probably most effective in tertian and quartan 
infections than in estivo-autumnal. It is thought that methyl- 
ene-blue affects especially the plasma of the parasites, and is 
consequently most effective in the stage where this cell element 
abounds. The drug causes a diminution of ameboid motion of 
the parasites and a splitting of the plasma substance into sev- 
eral spheric masses. 

Untoward symptoms caused by the administration of methyl- 
ene-blue are headache, nausea, vomiting, diarrhea, strangury, 
and albuminuria. These effects are less apt to supervene when 
a pure article is given. De Blasi 432 is of the opinion that it 
causes contractions of the pregnant uterus. The addition of 
2 or 3 grains of powdered nutmeg lessens the tendency to 
strangury. The patient should always be forewarned of the 
blue color imparted to the urine and feces. 

Thayer 433 reached the following conclusions after using" 
methylene-blue in a few cases : 

1. Methylene-blue has a definite action against malarial 
fever, accomplishing its end by destroying the specific organ- 
ism ; but it is materially less efficacious than quinine, failing to 
accomplish its purpose in many cases where quinine acts satis- 
factorily. 

2. The action appears to be rapid, the chills disappearing or 
the temperature, in the remittent cases, falling to normal dur- 
ing the first four or five days ; but later, however, if a sufficient 
number of organisms have resisted the drug, they appear to 
develop again directly under its influence, causing a return of 
the symptoms. 



TREATMENT 375 

3. Methylene-blue seems to have no advantages over quinine 
which would warrant its further use. 

Moore and Allison, 434 who treated 10 cases of malaria with 
20 grains daily of methylene-blue, give the following as their 
conclusions : 

1. Methylene-blue will destroy malarial parasites in many 
cases, but is less certain than quinine. 

2. Methylene-blue is probably most valuable in chronic cases, 
but has no advantage over quinine. 

3. The effects of methylene-blue are ordinarily more un- 
pleasant than quinine. 

4. It is useful in cases that cannot take quinine on account 
of some idiosyncrasy toward it. Its use in cases of pregnancy 
is undetermined. 

5. It is probably valuable in treating hematuric and hemo- 
globinuric fevers on account of its diuretic action; this has as 
yet to be determined. We have had no chance to test its use 
in such cases. 

6. We believe that quinine is quicker and more certain, and 
would rely upon it rather than upon methylene-blue. 

After its introduction in 1842 by Boudin arsenic enjoyed, 
until recently, considerable reputation in the treatment of 
malaria. The old school of physicians claimed results but 
little inferior to those with quinine. More recent observations 
show that if this agent has any value in the treatment of 
malaria it is in the chronic form. Whether its good effects 
here are chiefly upon the anemia and as a general tonic or 
whether it has some action upon the parthenogenetic cycle is 
not determined. Fowler's solution and the arsenous acid are 
the preparations usually employed. The dose at the beginning 
should be small and gradually increased. Upon the appearance 
of puffiness of the eyelids, colicky pains in the abdomen, and 
diarrhea the dose should be diminished or its use temporarily 
discontinued. The arsenous acid may well be combined with 
iron, quinine, and strychnine in the treatment of chronic 
malaria. 

Two recent preparations of arsenic, arrhenal or disodic 
methylarsenate, and sodium cacodylate have been vaunted as 



376 THE STUDY OF MALARIA 

antimalarials by Gautier and others. They are rich in arsenic, 
but less toxic. Both preparations have been used in cases 
where abortion threatened, and good results have been claimed. 
They are usually given hypodermically in doses of from 2 /i to 
i~y 2 grains daily. 

The benefits derived from atoxyl in the treatment of trypano- 
somiasis led to an investigation of its merits in malaria. 
Chemically, atoxyl is sodium aminophenyl arsenate, containing 
about 25 per cent, of arsenic and soluble, at 20° C, in 4.3 
parts of water. The usual dose is from one-third to 1 
grain, given every day or every other day, usually hypodermic- 
ally. 

Grosch 435 cured with atoxyl a case of malaria that obstinately 
resisted quinine for a long period. Fusco had satisfactory re- 
sults in 3 cases. Koch, in reporting his experience with atoxyl 
in the treatment of sleeping sickness, states that in cases that 
were complicated with malaria, usually of the estivo-autumnal 
variety, the malarial parasites diminished markedly, but were 
not so decidedly influenced by the drug as were the trypano- 
somes. 

Slatineano and Galesesco, employing large doses of atoxyl 
in 15 cases of malaria, had 10 cures and 5 failures. The fail- 
ures were experienced mostly with double infections. Georg- 
opulos, after its use in 14 cases, reported that the paroxysms 
ceased, the spleen diminished in size, the parasites disappeared 
from the blood, and the general condition of the patient im- 
proved. In 6 cases treated by Gonder and Dapas the patients 
improved during the treatment ; in 2 cases the splenic enlarge- 
ment diminished considerably, but in only 1 case did the para- 
sites disappear entirely. The resistance of the gametes, espe- 
cially the macrogametes, to the drug was noteworthy. 436 Vas- 
sal 437 claims good results, especially in malarial cachexia, by 
the use of atoxyl with the quinine. 

While the experience of the writer with atoxyl has been 
limited, he believes that it is a valuable adjuvant to quinine in 
the cases where the latter is insufficient, particularly in cases 
of cachexia and extreme anemia. Its good effect in these cases 
may be due to the increased amount of arsenic which may be 



TREATMENT 377 

administered in this form. In employing atoxyl its possible 
toxic effects should not be lost sight of. 

The value of opium in the treatment of malaria was discov- 
ered accidentally by Lind, 71 in 1766. He says: 

"The effects of opium given in the hot fit of an intermit- 
ting fever are : ( 1 ) It shortens and abates the fit, and this, 
with more certainty than an ounce of bark, is found to remove 
the disease; (2) it generally gives a sensible relief to the head, 
takes off the burning heat of the fever, and occasions a profuse 
sweat; this sweat is attended with an agreeable softness of 
the skin instead of the disagreeable burning sensation which 
usually affects patients sweating in the hot fit, and is more 
copious than in those who are not under the influence of opium ; 
(3) it often produces a soft and refreshing sleep to patients 
before harassed with the fever, from which they awake bathed 
in sweat, and in a great measure free from complaint. 

"I have always observed that the effects of opium are more 
uniform and constant in intermitting fevers than in most other 
diseases, and are then more quick and sensible than those of 
most other medicines. An opiate thus given, soon after the 
commencement of the hot fit, by abating the violence and less- 
ening the duration of the fever, preserves the constitution in 
a great measure uninjured. Since I have used opium in agues, 
a dropsy or jaundice has seldom attacked any of my patients in 
these diseases." 

Opium is not only effective against certain symptoms of 
malaria, but it has been shown by Drake 65 and others to possess 
antiperiodic virtue. This is, in all probability, due to the 
narcotine contained. For this reason opium, in the form of 
the powder, Dover's powder, laudanum, or paregoric, is more 
effective than morphine. In order to test the value of narcotine 
as compared to quinine, Duncan 438 treated 78 cases of malaria 
with quinine, with an average duration of fever of 2.1 1 days 
and 20.5 per cent, of failures ; with 66 cases of malaria treated 
with narcotine the average duration of the fever was 2.77 days 
and the per cent, of failures only 1.06. The immunity of 
opium smokers to malaria has been remarked upon by a num- 
ber of tropic physicians. 



378 THE STUDY OF MALARIA 

A large number of other substances have been recommended 
as substitutes for quinine. The chief of these are phenocoll, 
eucalyptus, salicin, salicylic acid, sodium hyposulphite, etc. 
Their antimalarial value, if, indeed, they possess any, is so 
slight as to render a detailed consideration not worth the 
while. 

The serum treatment of malaria has not yet reached the 
stage of practical utility. Indeed, the experiments of Ford 140 
alone have resulted in the isolation of an antitoxin. In his 
first series of 9 cases of benign tertian malaria 7 were cured, 
1 was temporarily benefited, while in the other the result was 
negative. In his second series of 20 cases of benign tertian 
17 were cured, while 3 were apparently quite uninfluenced. 

Critzmann 86 had several cachectic patients eat three times 
daily 50 grams of chopped beef spleen mixed with the yolk 
of an egg and 10 grams of bone-marrow. Burot and Le- 
grand 225 used the same treatment in numerous cases of cachexia 
in the hospital of Rochefort. In the course of about fifteen 
days the patient acquired a disgust for the repast. While the 
preparation had no effect upon the fever, it seemed to act as 
a reconstituent. 

More recently Carpenter 439 claims remarkable success in the 
treatment of malaria with powdered splenic extract in the dose 
of 5 grains every two to four hours, preferably in capsules. 
He says : "In more than six years' continuous experience and 
in the treatment of hundreds of cases of malarial infections 
of all types, both simple and complicated by all sorts of condi- 
tions, not a single case has been met with which did not yield 
to this remedy." He further states that it is equally as reliable 
a remedy as quinine. 

The Treatment of Pernicious Malaria. — There are cer- 
tain cases apparently on the borderline between benign malaria 
and pernicious malaria of the cerebral type which may cause 
hesitation as to the mode of administration. In these cases, 
usually in children, the patients, though stupefied, or even semi- 
comatose, can be aroused and made to swallow and usually 
retain the medicine. In such cases, if the patient can be 
watched, the quinine may be given in solution by the mouth. 



TREATMENT 379 

If vomited or if the symptoms do not rapidly improve, the drug 
in dilute solution should be injected intramuscularly. Where 
the injection mode is chosen it is advisable to supplement this 
with oral administration of the solution where it can be swal- 
lowed, and even the rectum may be employed also. 

As previously stated, quinine for intramuscular injection 
should be in dilute solution; 15 grains to 2^2 drams of water 
is a suitable proportion. The gluteal region, above the ischial 
tuberosities, is the best site for injection. In pernicious cases 
about 15 grains is the quantity to be used at first injection. 
Subsequent doses may be from 5 to 10 grains injected every 
six to eight hours as needed. The technic of such injections 
has already been given. 

Just as antisyphilitics may cause the gumma to melt rapidly 
but are powerless to restore the tissue it has destroyed, so 
quinine has its limitations in the therapeutics of malaria. It 
should be borne in mind that in its relation to the parasites 
quinine is a toxin, but not an antitoxin. It is possible that 
where the parasites are accumulated to the extent of throm- 
bosis the quinine in solution in the blood does not reach them 
in toxic quantities, and where perivascular exudation, hemor- 
rhage, and necrosis have resulted from these thrombi the anni- 
hilation of the parasites avails nothing. This is corroborated 
by those cases ending fatally, notwithstanding a rapid disap- 
pearance of the parasites, and in which post mortem these 
secondary changes are found. All that can be expected of 
quinine is to destroy the parasites, and this it may fail to 
accomplish from not being absorbed or not being present in 
the blood in sufficient quantities or at the time when the para- 
sites are most susceptible to its action, or on account of throm- 
botic occlusions it may not gain access to the parasites causing 
the symptoms. Quinine is probably a true specific in those 
cases of pernicious malaria only in which, in the absence of 
irreparable changes due to toxins or to thrombi, the prompt 
destruction of the parasites would be attended by an almost 
simultaneous cessation of symptoms. 

Other than the specific treatment there are important symp- 
tomatic indications to be met. 



380 THE STUDY OF MALARIA 

In cases with high temperature and hot dry skin cooling 
baths should be used. For heart depression strychnine or 
digitalis are useful. 

In the cerebral types the ice-bag to the head is called for 
and an active cathartic should be given if possible. Where this 
cannot be swallowed, a drop of croton oil on the back of the 
tongue may be tried. If delirium is marked, a solution of 
chloral and the bromides should be given by the rectum. Where 
there are convulsions, chloral and bromides by the rectum, 
morphine hypodermically, or even inhalations of chloroform 
may be necessary. Bell employed lumbar puncture in a case 
of malarial coma to relieve the increase in the cerebrospinal 
fluid which usually exists in these cases, but the result was 
disappointing. 

In algid attacks for the relief of cold surface and dyspnea, 
especially if choleraic symptoms are present, nothing is so suit- 
able as a combination of morphine and atropine. The heart 
usually requires stimulation by strychnine and digitalis. Hypo- 
dermics of ether may be necessary. If dysenteric symptoms 
arise they should be treated with opium and bismuth, together 
with saline irrigations. 

If complications appear they should receive appropriate 
treatment. 

During convalescence a tonic of arsenic, strychnine, iron, 
and quinine is usually indicated. In cases where it is feasible, 
a change of climate should be ordered until recovery is thor- 
oughly established. 

Treatment of Hemoglobinuria Fever. — The discussion of 
the treatment of hemoglobinuric fever has probably been pro- 
ductive of more harsh and prejudiced controversies than has 
any other question in therapeutics. The bone of contention 
is quinine. 

It is unnecessary to review the history of the discussions 
or to rehearse the arguments for or against the etiologic rela- 
tion of quinine to blackwater fever. No valid conclusion can 
be reached except through results of a large series of cases 
treated with and without quinine. The collection recorded 
under Prognosis shows a mortality of 25.9 per cent, in cases 



TREATMENT 38 1 

treated with quinine, and ii.i per cent, in cases in which no 
quinine was used. This number of cases probably eliminates 
all errors and should be convincing. 

While the results of the series prove that the mortality is 
higher under the routine treatment with quinine, they should 
not be taken to exclude absolutely the use of quinine in some 
cases of hemoglobinuric fever, for under certain circumstances 
quinine may be of value. It is difficult — in fact, sometimes 
impossible — to sa)' whether quinine is indicated or contraindi- 
cated in a certain case. 

Mannaberg 1411 gives the following general rules to aid a 
decision : 

1. When, without quinine preceding-, hemoglobinuria oc- 
curs and the blood examination shows the presence of malarial 
infection, quinine is undoubtedly to be exhibited. 

2. When the hemoglobinuria occurs after one dose of 
quinine, while the anamnesis shows that the patient previously 
took quinine without bad effect, and the parasites are present 
in the blood, quinine is also to be exhibited. If a paroxysm 
of hemoglobinuria should follow within a few hours, the repe- 
tition of the drug should be made dependent upon whether or 
not the parasites have in great part disappeared. In the former 
case the quinine may be stopped, at least for a time. But if 
the blood examinations show that the parasites have increased 
in number the quinine is to be continued. 

3. When the anamnesis shows that the patient suffered pre- 
viously from hemoglobinuria following quinine and the blood 
examination is negative, quinine is to be absolutely avoided. 

4. When the case manifests a severe malarial infection 
(numerous parasites on examination) and at the same time an 
assured intolerance to quinine in the shape of hemoglobinuria 
the decision is very difficult. 

Marchiafava and Bignami 22 believe that the only guide indi- 
cating to the physician whether to give or to withhold quinine 
ought to be the result of a blood examination. 

Bastianelli's 101 canon is as follows : . 

1. If a hemoglobinuria occurs during a malarial paroxysm 
and parasites are found in the blood quinine should be given. 



382 THE STUDY OF MALARIA 

2. If parasites are not found in the blood quinine should not 
be given. 

3. If quinine has already been given before the hemoglo- 
binuria has appeared and no parasites are found, its use should 
be suspended ; but if parasites persist it should be continued. 

Thayer 98 states his rules, modified from Bastianelli, thus : 

1. If the attack occurs spontaneously with a malarial parox- 
ysm, the blood showing the presence of parasites, quinine 
should be freely administered hypodermically or intravenously. 

2. If the parasites have disappeared, either as a result of 
the paroxysm itself or of doses of quinine already given, it 
may be as well to abstain, at least for a time, from the admin- 
istration of the drug. It cannot ameliorate the further course 
of the paroxysm, and the possibility, if it has been already 
given, that the symptoms may be in part due to quinine may 
be thought of. 

3. If an attack arise in the middle of an ordinary malarial 
infection, after taking quinine, it is best to abstain, for a time, 
at any rate, from the further use of the drug. That which has 
been given may have been enough to control the affection. 

4. If, however, in an attack coming on after quinine, the par- 
asites continue to develop, quinine should be again adminis- 
tered, despite the slight possibility of its injurious action. The 
dangers from the further development of the parasites are 
probably the greater. 

5. In postmalarial hemoglobinuria quinine is, of course, use- 
less. 

The following- rules of Vedy 213 are practical : 

1. If living parasites (not merely evidence of their former 
existence, pigment) are detected twenty-four hours after the 
beginning of the attack 80 centigrams of a salt of quinine 
may be injected subcutaneously. 

2. If the parasites are not visible do not administer quinine. 

3. If in doubt, that is to say, if the microscopic examination 
of the blood cannot be made, do not give quinine. 

It may be seen that the authorities quoted lay great stress 
on the presence of the parasite as a guide to the administration 
of quinine. The writer, however, cannot agree with those who 



TREATMENT 383 

hold that quinine should be exhibited in every case where the 
microscopic examination shows the presence of parasites. It 
has been shown conclusively that parasites are present in a 
very large proportion of cases examined early. It has also 
been shown that in an equally large number of cases the para- 
sites disappear spontaneously. In these cases quinine is, to 
say the least, superfluous. 

In the writer's opinion, the only conditions in which quinine 
is indicated are: first, where the parasites show no tendency 
to disappear after forty-eight hours from onset; second, in 
the infrequent cases of intermittent hemoglobinuria where the 
outbreak corresponds with parasitic sporulation. 

If it is decided to give quinine it should be injected, in dilute 
solution, into the muscles as directed for the treatment of 
pernicious malaria. Given by the mouth it upsets the stomach 
and may not be absorbed. 

Even in cases of mildest onset the patient should be confined 
to bed from the start, and should be kept quiet either by 
suasion or by sedatives. Sudden death on slight exertion some- 
times occurs. The patient should not be transported from one 
place to another; the Plehn brothers observed anuria as a 
frequent consequence of moving patients from place to place. 
Chilling of the body, especially when the temperature is low, 
should be carefully avoided. When vomiting is not a promi- 
nent feature liquid nourishment may be given freely; butter- 
milk and albumen water are the most suitable. Sweet milk is 
often ejected as a thick curd, molded ropy by the esophagus 
in the act of vomiting. Animal broths, barley and oatmeal 
water, lemonade, and orange juice are allowable. Rectal ali- 
mentation is unsatisfactory. 

There is no specific. M ethyl ene-blue has proved disappoint- 
ing. Besides being a renal irritant, it masks the color of the 
urine, a most serious objection. Salicylic acid probably has 
no effect further than to upset the stomach and increase the 
discomfort. With the false idea that a hemorrhage has to be 
checked, gallic and tannic acids, ergot, and similar drugs are 
frequently given ; these cannot possibly be of any benefit. Car- 
bolic acid and other renal irritants should not be used. 



384 THE STUDY OF MALARIA 

The bowels should be moved early and often, and calomel 
possesses advantages over other purgatives; it is more easily 
retained, is a bland diuretic, and is the best of intestinal anti- 
septics. Too large doses are usually advised ; 3 to 5 grains 
are, as a rule, sufficient, repeated pro re nata. 

Quennec's i4:0 chloroform treatment has been successful in 
some hands. The originator claims for the method three 
points of value : 

1. Controls vomiting. 

2. Increases output of urine. 

3. Diminishes albuminuria. 

He treated more than 50 cases with no mortality. The fol- 
lowing is his formula : Chloroform, 6 grams ; gum arabic, 8 
grams; sweetened water, 250 grams. This amount is used 
daily, a sip taken every ten minutes. In addition, Quennec 
used quinine, 1 gram daily subcutaneously, and sulphate of 
soda and senna by rectum. The excessive administration of 
chloroform might be harmful, as it is a cardiac depressant, 
renal irritant, and lowers the blood pressure. 

Cardamatis 206 gives ether in every case of hemoglobinuric 
fever. In ordinary cases he prescribes a teaspoonful in sweet- 
ened water every three hours, and increases the dose if the 
urine diminishes in quantity. In cases of suppression he gives 
as much as a teaspoonful every hour, at the same time inject- 
ing hypodermically 1 cc. every two or three hours. . He main- 
tains that by this means the pulse is strengthened, precordial 
anxiety, dyspnea, and vomiting are relieved, and a profuse 
diuresis is provoked. 

The writer has had no experience with ether in the treatment 
of blackwater fever, but would consider it too irritating to the 
kidneys for general use. 

Hearsey 266 used with good results a modification of Stern- 
berg's yellow-fever treatment. The original Sternberg for- 
mula is: sodium bicarbonate, 150 grains; mercury perchloride, 
one-third grain ; water, 2 pints. Sig. : 1 ^2 ounces every hour. 
Hearsey gives sodium bicarbonate, 10 grains ; liquor hydrargyri 
perchloridi, 30 minims; every two to three hours. 

A method of treatment recently introduced and extrava- 



TREATMENT 385 

gantly extolled by its originator is that of Vincent.** 1 This 
writer maintains that calcium chloride is not only a preventive, 
but has extraordinary curative powers. During the attack from 
4 to 6 grains are given daily by the mouth, or from I to 2 
grams dissolved in normal salt solution hypodermically. He 
asserts that it acts as an antihemolysin, and that in persons in 
whom an attack of blackwater may be provoked at will by 
a dose of quinine, the previous administration of calcium chlo- 
ride will forestall the outbreak. It is worthy of mention that 
this drug has been used successfully in paroxysmal hemoglo- 
binuria by Saundby, and in hemophilia by Wright and others. 

The writer has recently employed calcium chloride in 6 
cases, of which 3 ended fatally. The series is too small to 
permit of very definite conclusions as to results of treatment, 
but it would appear that the results claimed by Vincent were 
not obtained. The 3 fatal cases were in persons whose health 
was probably not more undermined from previous malaria or 
other causes than the average patient who is attacked with 
hemoglobinuric fever. It is worthy of note that the cause 
of death in these 3 cases was not syncope nor suppression, 
but exhaustion due directly to hemolysis, the very process 
which calcium chloride was used to combat. No treatment 
other than supportive was used which might modify the anti- 
hemolytic effects of the calcium chloride. 

Hyposulphite of soda introduced into the treatment of mala- 
rial conditions by Polli, 442 in 1867, has been used extensively 
in the treatment of hemoglobinuria. Its use is probably not 
attended with any signal results. O'Sullivan-Beare 443 used 
with good results a decoction of the root of cassia beareana, 
a native plant. Gouzien employed an infusion of the leaves 
of cassia occidentalis. 

Teas made from the leaves of folia combreti alti and of 
aphloia theceformis are also highly recommended. 86 

The fever does not usually run sufficiently high to call for 
treatment. The coal-tar preparations should be assiduously 
avoided. Cold baths may be productive of harm by increasing 
the blood destruction, but in hyperpyrexial cases sponging with 
tepid water may be resorted to. 

25 



386 THE STUDY OF MALARIA 

Vomiting, if not intense, is often benefited by a mustard 
plaster on the epigastrium. The fly-blister formerly used 
should be abandoned. Draughts of hot water or carbonated 
water sometimes assist in relieving this troublesome symptom. 
Cracked ice may be tried. Morphine hypodermically should 
be given unhesitatingly when other measures fail. Any evil 
effects are more than outweighed by its enabling the stomach 
to retain liquids. 

An important measure toward the prevention and relief of 
nausea and vomiting is to maintain the recumbent position. 
Medicine, water, and nourishment should be taken through 
a drinking tube or the ordinary invalid's cup, and the bed- 
pan or urinal should be used when evacuating the bowels or 
bladder. 

It is imperative to allay the restlessness often present in these 
cases. For this purpose chloral and bromide of soda by 
rectum, morphine hypodermically, or sulphonal or small doses 
of chloroform by mouth are useful. 

Probably the most important indication in the treatment is 
the prevention of suppression. Medicinal diuretics usually do 
harm. One, turpentine, widely used in some sections, should 
be condemned in the strongest terms. It is one of the most 
violent renal irritants, and in some persons small doses may 
cause suppression or hematuria. Water is the best diuretic, 
and as much should be given by mouth as will be retained. 
Lewis, 1,92 of North Carolina, was the first to recommend the 
use of normal salt solution by hypodermoclysis and by the 
rectum in the treatment of hemoglobinuric fever, though Lav- 
eran 1 attributes the priority to Gouzien. The latter recom- 
mends the daily injection of 100 to 300 grams of a nine-tenths 
per cent, solution, in conjunction with the rectal injection of 
200 grams, four to six times in twenty-four hours. The use 
of salt solution is the very best means of combating and treat- 
ing anuria. It is probably better to use a hypertonic solution. 
In mild cases where the urine is free the rectal use is usually 
sufficient, but in cases where suppression threatens or is immi- 
nent the solution should be used subcutaneously or intra- 
venously and in larger quantities and oftener than advised by 



TREATMENT 387 

Gouzien. Mild counterirritation over the region of the kidneys 
may be tried. 

Werner, 4 * 4 in 1902, suggested nephrotomy for anuria. Such 
an operation has been recorded in only three instances. Zie- 
mann 48 mentions a case in a young female patient in whom 
suppression had existed two days. The capsule of the right 
kidney was split and peeled off to the hilum and nephrotomy 
performed through the convexity of the organ. The operation 
was well borne, and subsequently 200 cc. of cloudy, albuminous 
urine was voided from the bladder. During the following 
days complete suppression recurred, and the patient died. 

In Kruger's 445 case decortication of one kidney was done 
five days after the onset of anuria, and, although the secretion 
of urine was profusely reestablished, the patient died of pro- 
gressive weakness. 

Kiilz 446 reports a case in a man during his second attack. 
Three and a half days after the onset of anuria nephrotomy 
upon one kidney was performed through Simon's incision. 
Vomiting, which was formerly uncontrollable, ceased imme- 
diately. Three hours after the operation 30 cc. of blood were 
voided from the bladder. In eight hours the dressing was 
saturated with bloody icteric urine, which necessitated chang- 
ing the dressing every three hours. Twenty-four hours after 
the operation the patient died. Though a microscopic examina- 
tion of the kidney could not be made, upon gross inspection 
the nephrotomized kidney appeared much more nearly normal 
than the other. 

Supportive measures are essential. Alcohol in all its forms 
is inadmissible. Strychnine is useful, and should be given 
hypodermically when circumstances permit. Digitalis has 
proved serviceable in the writer's hands. Doering 187 had good 
effects from strophanthus. The aromatic spirits of ammonia 
and hypodermic injections of ether have been recommended. 
Transfusion of blood has been used, it is said, with excellent 
results. The elder Plehn 61 ' says that he had four attacks, in 
which Kohlstock treated him with inhalations of oxygen, and 
that nothing else did him so much good. Unfortunately, this 
method of treatment is not often possible in private practice. 



388 THE STUDY OF MALARIA 

The after-treatment should have a care for the diet, which 
should be non-nitrogenous and consist largely of liquids at 
first. A tonic of organic iron is indicated, and digestive dis- 
orders when present should receive appropriate treatment. 

A question of practical importance is, how soon after the 
attack to begin the administration of quinine. A dose given 
too early might possibly, in some persons, precipitate hemol- 
ysis. On the other hand, delay may permit an outbreak of 
malaria accompanied by hemoglobinuria. Upon the ground 
that most of the sensitive cells have succumbed during the at- 
tack and that the newly formed cells are probably more sus- 
ceptible than those that have withstood the attack, the writer 
is of the opinion that quinine should be begun, carefully at 
first, a short time after the attack has subsided and before 
blood regeneration is fairly established. One grain of quinine 
three times daily, increased gradually every other day, is a 
safe procedure. If the temperature rises or the urine becomes 
distinctly darker no further attempt to increase the dose should 
be made. 

In the present state of our knowledge it is probably Utopian 
to discuss the treatment of hemoglobinuric fever by antihemo- 
lytic sera, but such has recently been successfully accomplished 
by Widal and Rostaine 447 in paroxysmal hemoglobinuria. 

REFERENCES 

1. Laveran : Traite du Paludisme, Paris, 1907. 

2. New Orleans Med. and Surg. Jour., iv, 563, 1848. 

3. King : Popular Science Monthly, Sept., 1883. 

4. Crosse : Blackwater Fever, London, 1899. 

5. Plehn : Die Kamerun Kiiste, Berlin, 1898. 

6. Mense : Arch, fur Schiffs.- u. Trop. Hyg., iii, 4. 

7. Kohlbrugge : Arch, f iir Schiffs.- u. Trop. Hyg., iii, 2. 

8. Cited by Mense (6). 

9. Sambon : The Practitioner, March, 1901. 

10. Cited by Sternberg (73). 

11. Cummings : N. O. Med. News and Hosp. Gaz., vi, 811. 

12. Faget : N. O. Med. Jour., Oct., 1868. 

13. Osborne : Ibid., 1868, 644. 

14. Osborne: Ibid., xxii, 61. 

15. Ghent: Richmond and Louisville Med. Jour., v, 271. 

16. Cited by Cardamatis (206). 

17. Johnson : Influence of Tropical Climates, etc., New York, 1826. 

18. Cleghorn: Diseases of Minorca, London, 1762. 

19. Hirsch : Handbook of Geog. and Hist. Pathology, London, 1883, vol. i. 

20. Cited by Rogers (44). 

21. Ramazzini : Sur l'Abus du Quinquina, Paris Reprint, 1905. 



REFERENCES 389 

22. Marchiafava and Bignami : Malaria, New York, 1900. 

23. Medizinal Berichte iiber die Deutschen Schutzgebiete, 1903-04. 

24. A. Plehn : Arch, fur Schiffs.- u. Trop. Hyg., vii, 12. 

25. Moore: Jour. Trop. Med., March 15, 1902. 

26. Curry: Bost. Med. and Surg. Jour., Nov. 23, 1899. 

27. Scheube : Die Krankheiten der Warmen Lander, Jena, 1903. 

28. Charity Hospital Reports, New Orleans, 1906, 1907. 

29. Thayer and Hewetson: The Malarial Fevers of Baltimore, Baltimore, 

1895. 

30. Kendall : Jour. Am. Med. Assoc, 46, 1270. 

31. Gray and Low : Brit. Med. Jour., Jan. 25, 1902. 

32. Gorgas : Ann. Rep. Dept. Sanitat. Isthmian Canal Commis., 1907-08. 

33. Koch : Deut. Med. Woch., Feb. 2, 1899. 

34. Koch : Deut. Med. Woch., Sept. 14, 1899. 

35. Cardamatis and Diamessis : La Grece Med., Nov. 1-15, 1906. 

36. Mollow : Malaria, vol. i, 75. 

37. Atti Delia Soc. per gli Studi della Malaria, Rome, 1901-08. 

38. Wright : The Malarial Fevers of British Malaya, London, 1902. 

39. Craig: Rev. in Jour. Trop. Med., June 15, 1904. 

40. Hope: Jour. Trop. Med., June 15, 1904. 

41. Williamson : Brit. Med. Jour., Sept. 14, 1901. 

42. Koch : Deut. Med. Woch., April 26, 1900. 

43. Chamberlain: Jour. Am. Med. Assoc, 46, 304. 

44. Rogers : Fevers in the Tropics, London, 1908. 

45. Buchanan : Mai. Fev. and Mai. Parasites in India, Calcutta, 1903. 

46. Cited by Buchanan (45). 

47. Tsuzuki : Malaria, vol. i. 

48. Ziemann : Mense's Handbuch der Tropenkrankheiten, Leipzig, 1906. 

49. Medizinal Berichte iiber die Deutschen Schutzgebiete, 1904-05 and 

1905-06. 

50. Thiroux et dAnpreville, Le Paludisme au Senegal, Paris, 1908. 

51. Medizinal Berichte iiber die Deutschen Schutzgebiete, 1904-05. 

52. Ibid. 1905-06. 

53. Otto: Deut. Med. Woch., 1902, No. 4. 

54. Brault: Janus, Nov. 15, 1903. 

55. Coste: Rev. in La Presse Med., Sept. 12, 1906. 

56. Wellman : Jour. Am. Med. Assoc, 45, 1736. 

57. Reports to the Malarial Committee, 5th Series, London, 1901. 

58. F. Plehn: Deut. Med. Woch., 1901, p. 838. 

59. Manson: Tropical Diseases, London, 1903. 

60. Johnson: Jour. Trop. Med., Dec. 15, 1900. 

61. F. Plehn: Deut. Med. Woch., 1895, 25-27. 

62. A. Plehn: Arch, fur Schiffs.- u. Trop. Hyg., iii, 4. 

63. Jour. Am. Med. Assoc, 48, 1195. 

64. Masterman : Brit. Med. Jour., Feb. 10, 1906. 

65. Drake : Principal Diseases of the Valley of North America, Cincin- 

nati, 1850. 

66. Davidson, Hygiene and Diseases of Warm Climates, Edinb., 1893. 

67. Cited by Marchiafava and Bignami (22). 

68. Atti della Societa per gli Studi della Malaria, Rome, 1907. 

69. Koch : Deut. Med. Woch., Feb. 1, 1900. 

70. Craig: Estivo-autumnal Malaria, New York, 1901. 

71. Lind : Diseases Incidental to Europeans in Hot Climates, Phila., 181 1. 

72. Watson: Practice of Physic, Phila., 1854. 

73. Sternberg: Malaria and Malarial Diseases, New York, 1884. 

74. La Roche : Pneumonia and Malaria, Phila., 1854. 

75. Maurel : Maladie Paludeennes a la Guyane, Paris, 1883. _ 

76. Med. and Surg. History of the War of the Rebellion, iii, med. vol. 

77. Smith: Brit. Med. Jour., Dec. 17, 1898. 

78. Koch: Deut. Med. Woch., Dec. 6, 1900. 

79. Cited by Ziemann (48). 



39° THE STUDY OF MALARIA 

80. Celli : La Malaria Secondo le Nuove Ricerche, Rome. 

81. Erni : Arch, fur Schiffs.- u. Trop. Hyg., June, 1899. 

82. Atti della Societa per gli Studi della Malaria, Rome, 1906. 

83. Ibid., 1908. 

84. Ibid., 1904. 

85. Jour. Am. Med. Assoc., 51, 916. 

86. Cited by Laveran (1). 

87. Strachan: Brit. Med. Jour., March 18, 1905. 

88. Ross : Brit. Med. Jour., Sept. 14, 1901. 

89. Panse : Arch, fur Schiffs.- u. Trop. Hyg., 1902, No. 12. 

90. Cited by Ruge (158). 

91. Craig: Yale Med. Jour., June, 1907. 

92. Schellong: Die Malariakrankheiten, Berlin, 1890. 

93. Hadjimichalis and Cardamatis, Ann. Trop. Med. and Par., ii, 2. 

94. Report to the Malarial Committee, 6th Series, London, 1902. 

95. Russell: Malaria and Injuries of the Spleen, Calcutta, 1880. 

96. Cited by Mannaberg (141). 

97. Felkin : Edinb. Med. Jour., June, 1889. 

98. Thayer: Lectures on the Malarial Fevers, New York, 1901. 

99. A. Plehn: Die Malaria der Afrikanischen Negerbevolkerung, Jena, 

1902. 

100. Pezopoulos and Cardamatis : Arch, de Med. des Enf ants, Jan., 1907. 

101. Cited by Manson (59). 

102. Winslow : Boston Med. and Surg. Jour., May 27, 1897. 

103. Peters : Johns Hopkins Hosp. Bull., June, 1902. 

104. Moffatt : Brit. Med. Jour., May 4, 1907. 

105. Cited by Crespin (144). 

106. Hitte : These de Montpellier, 1902. 

107. Holt : Diseases of Infancy and Childhood, New York, 1908. 

108. Economous : Bull, de la Soc. d'Obstet., x, 70, 1907. 

109. Bell: Jour. Am. Med. Assoc, 51, 1993. 
no. Cited by Thayer and Plewetson (29). 
in. Jeffries: Med. Record, 57, 654. 

112. Daniels: Brit. Med. Jour., Jan. 26, 1901. 

113. Stephens and Christophers: Thomp. Yates Lab. Rep., v. i. 

114. Cited by Howard (122). 

115. Cited by Galli-Vallerio et de Jongh (124). 

116. Banks : The Philippine Journal of Science, Dec, 1907. 

117. Cited by Austin, The Practitioner, March, 1901. 

118. Stephens and Christophers: Practical Study of Malaria, London, 1904. 

119. Giles: The Gnats or Mosquitoes, London, 1902. 

120. Coquillett : Class, of the Mosq. of North and Middle America, Wash., 

1906. 

121. Sambon : Brit. Med. Jour., Sept. 24, 1908. 

122. Howard: Mosquitoes, New York, 1902. 

123. Nuttall : Brit. Med. Jour., Sept. 14, 1901. 

124. Galli-Vallerio et de Jongh : Manuel pour la Lutte, etc., Paris, 1906. 

125. Pressat : Le Paludisme et les Moustiques, Paris, 1905. 

126. Mitchell: Mosquito Life, 1907. 

127. Eyesell : Arch, f iir Schiffs.- u. Trop, Hyg., xi, 6. 

128. Woldert : Jour. Am. Med. Assoc, 50, 1249. 

129. Cited by Stephens and Christophers (118). 

130. Ewing: Jour. Exp. Med., March 25, 1901. 

131. Cited by Mannaberg (404). 

132. Cited by Ewing (130). 

133. Cited by Schaudinn (134). 

134. Schaudinn: Arbeiten aus den Kaiserl. Ges. Amt, 19, 2. 

135. Maurer : Centralbl. fiir Bakt., Parasit., etc., Nov. 5, 1902. 

136. Bliiml and Metz : Arch, fiir Schiffs.- und Trop. Hyg., xii, 249. 

137. Craig: International Clinics, 17th Series, Hi. 

138. Cited by Craig (70). 



REFERENCES 



391 



139. Cited by Thayer (98). 

140. Ford: Jour. Am. Med. Assoc, 48, 133; Med. Record, 66, 1001. 

141. Mannaberg: Malarial Diseases, Phila., 1905. 

142. Rosenau et al.: Exp. Stud, in Yellow Fever and Malaria, Wash., 

I905- 

143. Koch : Deut. Med. Woch., May 3, 1900. 

144. Crespin : Precis du Paludisme, Paris, 1905. 

145. Bell : The Lancet, Aug. 24, 1900. 

146. Santos : L'Influence de l'lmpaludisme, etc., Rio de Janeiro, 1888. 

147. Atti della Societa per gli Studi della Malaria, Rome, 1902. 

148. Thornhill: Indian Med. Gaz., March, 1898. 

149. Cited by Burot et Legrand (212). 

150. Atti della Societa per gli Studi della Malaria, Rome, 1901. 

151. Billet : Revue de Medicine, Dec, 1902. 

152. Sims: Jour. Trop. Med., Jan. 15, 1902. 

153. Rees : Brit. Med. Jour., Feb. 10, 1900. 

154. Satterlee: New York Med. Jour., April 11, 1908. 

155. Hall: Denver Med. Times, April 1908. 

156. Neer: Jour. Am. Med. Assoc, 50, 1890. 

157. Homem : Pernicious Fever, Detroit, 1904. 

158. Ruge : Einfiihrung in das Studium der Malariakrankheiten, Jena, 1906. 

159. Cited by Le Dantec (226). 

160. Wurtz and Thiroux : Diag. et Setn. des Malad. Trop., Paris, 1905. 

161. Roux: Maladies des Pays Chauds, Paris, 1886. 

162. Marchiafava and Bignami : Summer and Autumn, Mai. Fever, London, 

1894. 

163. Van der Scheer : Virchow's Archiv., 139, 1. 

164. Craig: Osier's Modern Medicine, Phila., 1907, vol. i. 

165. Crespin : La Caducee, May 2, 1903. 

166. French: New York Med. Jour., May 23, 1896. 

167. Hunt : New York Post-Graduate, Nov., 1906. 

168. Cited by Sutherland: Memphis Med. Monthly, July, 1905. 

169. Ficucci : Rev. in Med. Record, 71, 870. 

170. Fenner : N. O. Med. and Surg. Jour., Dec, 1903. 

171. A. Plehn : Beitr. zur kennt. der Trop. Malaria, Berlin, 1896. 

172. Koch: Arbeiten aus den Kaiserl. Gesundh. Amt., 14, 2. 

173. Cited by Rho : La Malaria, Turin, 1896. 

174. Barker : Study of Some Fatal Cases of Malaria, Baltimore, 1895. 

175. Zeri : II Policlinico, April, 1904. 

176. Bloomberg and Coffin: Am. Med., Nov. 25, 1905. 

177. Ewing: Am. Jour. Med. Sci., Oct., 1001. 

178. Kelsch and Kiener : Maladies des Pays Chauds, Paris, 1889. 

179. Cited by Ewing (181). 

180. Ford : Med. Record, April 5, 1902. 

181. Ewing: Jour. Exp. Med., Feb. 5, 1902. 

182. Mercier : Le Paludisme Observe sous les Tropiques, Paris, 1905. 

183. Hertz : Ziemssen's Cyclopedia, New York, 1875, vol. ii. 

184. Hanley: Jour. Trop. Med., 1899, p. 85. 

185. Cited by F. Plehn (208). 

186. Curry: Jour. Am. Med. Assoc, 38, 1130. 

187. Doerring: Deut. Med. Woch., Nov. 14, 1895. 

188. Reynolds : Jour. Trop. Med., Jan., 1899. 

189. Goltman and Krauss: Memphis Lancet, Dec, 1898. 

190. Personal Communication. 

191. Cited by F. Plehn (5). 

192. Lewis: N. C. Med. Jour., March 5, 1899. 

193. Francez: N. O. Med. and Surg. Jour., July, 1902. 

194. Minos : Med. News, Nov. 24, 1883. 

195. McKay: Am. Pract. and News, June 1, 1902. 

196. Tyson: Med. News, May 12, 1883. 

197. Daniels: Laboratory Studies in Tropical Medicine, Phila., 1903. 



392 THE STUDY OF MALARIA 

198. Cardamatis : La Grece Medicale, April, 1900. 

199. Krauss : Memphis Med. Monthly, April, 1902. 

200. Deaderick: Memphis Med. Monthly, Aug., 1907. 

201. Mense : Arch, fiir Schiffs.- u. Trop. Hyg., June, 1899. 

202. Lipari: II Morgagni, Sept., 1889. 

203. Cited by Scheube (27). 

204. Cited by Burns (235). 

205. Tomaselli : La Intossicazione Chinica, etc., Catani, 1897. 

206. Cardamatis : La Fievre Bilieuse Hemoglobinurique, Paris, 1902. 

207. Foustanos : La Grece Medicale, April, 1900. 

208. F. Plehn : Arch, fiir Schiffs.- u. Trop. Hyg., iii, 6. 

209. Crosse : Brit. Med. Jour., Oct. 8, 1898. 

210. Banks : Jour. Trop. Med., Dec. 15, 1900. 

211. F. Plehn: Tropenhygiene, Jena, 1906. 

212. Burot and Legrand : Maladies du Soldat aux Pays Chauds, Paris, 

1897. 

213. Vedy: La Fievre Bilieuse Hemoglobinurique, etc., Brussels, 1907. 

214. McElroy : Memphis Med. Monthly, May and June, 1905. 

215. Brem : Jour. Am. Med. Assoc, Dec. 8-15, 1906. 

216. Howard : Jour. Trop. Med., March 1, 1907. 

217. Bassett-Smith : Jour. Trop. Med., 1907, x, 69. 

218. Hughes : Jour. Trop. Med., June, 1899. 

219. Manson : Brit. Med. Jour., May 16, 1903. 

220. Parker : Brit. Med. Jour., Sept. 9, 1899. 

221. Mowbray: The Lancet, Aug. 26, 1905. 

222. Schlayer : Deut. Med. Woch., July 10, 1902. 

223. Kleine: Brit. Med. Jour., Sept. 14, 1901. 

224. Koch: Jour. Trop. Med., July 15, 1899. 

225. Burot et Legrand : Therapeutique du Paludisme, Paris, 1897. 

226. Le Dantec : Pathologie Exotique, Paris, 1905. 

227. Cited by Kelsch and Kiener (178). 

228. Dryepondt and Vancampenhout : Jour de Med. de Bruxelles, 1899, 9. 

229. Bertrand : Ann. Soc. Med.-Chi. d'Anvers, Nov. and Dec, 1899. 

230. Mould : Brit. Med. Jour., Sept. 9, 1899. 

231. Haig : The Lancet, April 2, 1898. 

232. Cited by Mense : Archiv. fiir Schiffs.- u. Trop. Hyg., iii, 2. 

233. Cited by Marchiafava and Bignami (162). 

234. Cited by A. Plehn (62). 

235. Burns : Jour. Am. Med. Assoc, Nov. 17, 10, 1900. 

236. Crosse : The Lancet, Jan. 6, 1900. 

237. Thin: Brit. Med. Jour., Sept. 1, 1900. 

238. Ketchen : Brit. Med. Jour., Nov. 10, 1906. 

239. Ruge : Deut. Med. Woch., July 10, 1902. 

240. Woldert: New York Med. Jour., Feb. 23, 1895. 

241. Hartsock: New York Med. Jour., Sept. 13, 1902. 

242. Broden : Trav. du Lab. Med. de Leopoldville, Brussels, 1906. 

243. Cited by Cardamatis (244). 

244. Cardamatis : Progres Medical, 1902, Nos. 37-40. 

245. Virchow's Jahresbericht, bd., 1, 1907. 

246. Grattan : Jour. Royal Army Med. Corps, 1907, ix, 3, p. 237. 

247. Kulz : Arch, fiir Schiffs.- u. Trop. Hyg., xii, 242. 

248. Smith and Kilbourne, Texas or Southern Cattle Fever, Washington, 

1893. 

249. Orme : Jour. Trop. Med., Feb. 1, 1908. 

250. Cited by Crosse (4). 

251. Cited by Brem (215). 

252. Cited by Vedy (213). 

253. Cited by Koch: Arch, fiir Schiffs.- u. Trop. Hyg, June, 1899. 

254. Ellenbeck-Hilden, Beobachtungen iiber Malaria, Berlin, 1905. 

255. Legrain : Introd. a l'Etude des Fievres des Pays Chauds, Paris, 1899. 

256. Grail : Pathologie Exotique, Paris, 1900. 



REFERENCES 393 

257. Rossoni : II Morgagni, Jan., 1899. 

258. Heal: Jour. Trop. Med, Feb. 15, 1899. 

259. Stalkarrt: Brit. Med. Jour., Sept. 9, 1899. 

260. Hopkins : Dublin Jour, of Med. Sci., June, 1903. 

261. Cited by Crosse (236). 

262. Rankin : Brit. Med. Jour., Sept. 1, 1900. 

263. Moffatt : Brit. Med. Jour., Jan. 25, 1902. 

264. McElroy: Jour. Am. Med. Assoc., 41, 605. 

265. Dubose: Jour. Am. Med. Assoc, March 11, 1899. 

266. Hearsey, Brit. Med. Jour., Jan. 26, 1901. 

267. Shropshire: Jour. Am. Med. Assoc, 41, 600. 

268. Murri : Deut. Med. Woch., Feb. 20-27, 1896. 

269. Marsden : Brit. Med. Jour., Sept. 1, 1900. 

270. Boxer : Brit. Med. Jour., May 7, 1904. 

271. Cited by Koch (253). 

272. Transactions of the Epidemologic Society, 1892-93. 

273. Cited by Stalkarrt (259). 

274. Yersin : Compt. Rend. Soc Biol., Paris, 1895, "\ 447- 

275. Breaudat: Arch, de Med. Nav., 1896, 457. 

276. Collett: The Lancet, Dec. 28, 1904. 

277. Wasserman : Immune Sera, New York, 1904. 

278. Deaderick: Jour. Am. Med. Assoc, June 1, 1907. 

279. Christophers and Bentley : Blackwater Fever, Simla, 1908. 

280. Billings : Johns Hopkins Hosp. Bull., Oct., 1894. 

281. Krauss : Jour. Am. Med. Assoc, 43, 1202. 

282. Thayer : Am. Jour. Med. Sci., Nov.-Dec, 1898. 

283. Anders : Jour. Am. Med. Assoc, June 15, 1895. 

284. Atkinson : Am. Jour. Med. Sci., July, 1884. 

285. Cited by Wurtz and Thiroux (160). 

286. Brown: Jour. Ark. and Med. Soc, Dec 15, 1907. 

287. Cardamatis : Bull, de la Soc. de Med. de Gand., Feb., 1901. 

288. Morris : S. W. Med. Record, July, 1899- 

289. Cited by Roux (161). 

290. Cited by Hertz (183). 

291. Colin: Traite des Fievres Intermittentes, Paris, 1870. 

292. Kanellis and Cardamatis : Le Progres Medical, May 19, 1900. 

293. Craig: Med. Record, Feb. 15, 1902. 

294. Gillot: Semaine Med., Sept. 13, 1905. 

295. Wolf: New England Med. Monthly, Nov., 1903. 

296. Chamberlain: Bost. Med. and Surg. Jour., Jan. 11, 1905. 

297. Craig: Am. Med., Oct. 29, 1904. 

298. Ross and Daniels : Jour. Trop. Med., Feb. 15, 1902. 

299. Marchoux: Le Caducee, Aug. 20, 1904. 

300. Fiemsa and Schaumann : Studien iiber Chinin, Leipzig, 1907. 

301. Williams: Jour. Trop. Med., Dec 15, 1900. 

302. Mackie : The Lancet, Dec 6, 1898. 

303. Christophers and Bentley: Indian Med. Gazette, March, 1908. 

304. Cited by Legrain (255). 

305. Cohen: Am. Jour. Med. Sci., 136, 344. 

306. Rist and Boudet : La Presse Medicale, Dec. 4, 1907. 

307. Craig: Med. Record, Feb. 15, I9° 2 - 

308. Ziemann : Deut. Med. Woch., June 21, 1900. 

309. Wellman: Proc Am. Soc. Trop. Med., 1905. 

310. Annett, Dutton and Elliott : Brit. Med. Jour., Sept. 14, 1901. 

311. Triantaphyllides : La Grece Med., v. 11-12. 

312. Raymond: These de Montpelier. 1896. 

313. Jenness : U. S. Naval Med. Bull., Jan., 1908. 

314. Hemmeter: Am. Med., Nov. 14, 1903. 

315. Cohen and Rosenberger, Am. Jour. Med. Sci., August, 1904. 

316. Trans, of Assoc, of Am. Physicians, 1902. 

317. Palmer : The Lancet, Dec. 24, 1892. 



394 THE STUDY OF MALARIA 

318. Brault: Maladies des Pays Chauds, Paris, 1900. 

319. Messerer : These de Paris, 1886. 

320. Goltman : Memphis Med. Monthly, Nov., 1905. 

321. Moore: Am. Med., Dec. 28, 1901. 

322. Duprey: Jour. Trop. Med., Sept. 16, 1907. 

323. Cited by Behrmann : Berlin Klin. Woch., Aug. 24, 1885. 

324. Goth: Zeitschr. fur Geb. u. Gynak., vii, 1, 1881. 

325. Bonfils : Paludisme et Puerperalite, Paris, 1885. 

326. Williams : A Text-book of Obstetrics, New York, 1903. 

327. Glogner : Virchow's Archiv., 1895, 140, p. 481. 

328. Price : Am. Med., June 3, 1905. 

329. Da Costa : International Clinics, Series 1891, iii. 

330. Fornaca : II Policlinico, 1907, 51. 

331. Torti : Riforma Med., 1891, xii. 

332. Spiller : Am. Jour. Med. Sci., Dec, 1900. 

333. Ziemann : Arch, fur Schiffs.- u. Trop. Hyg., xii, 501. 

334. Winfield : New York Med. Jour., Aug. 2, 1902. 

335. Bastianelli and Bignami : Bull. d. Soc. Lancis, Rome, 1890, lx, x. 

336. Deaderick : Southern Med. Jour., Oct., 1908. 

337. Anders : Phila. Hosp. Reports, iv, 1895. 

338. Loffler : Deut. Med. Woch., 1901, No. 42. 

339. Valenti : II Policlinico, xiv, 48, 1907. 

340. Lioubenetzky : Semaine, Med., 1908, 18. 

341. Mallory and Wright : Pathological Technique, Phila., 1904. 

342. Cabot : Am. Med., Dec. 20, 1902 ; Bost. Med. and Surg. Jour., March 

24, 1904. 

343. Fornario : Deut. Med. Woch., Jan. 22, 1903. 

344. McElroy: Memphis Med. Monthly, Nov., 1902. 

345. A. Plehn: Weiteres iiber Malaria, etc., Jena, 1901. 

346. Delaney: Brit. Med. Jour., March 28, 1903. 

347. Vincent : Ann. de l'lnstitut. Pasteur, Dec. 25, 1897. 

348. Ross : The Lancet, Nov. 17, 1906. 

349. Ross : The Lancet, Sept. 28, 1907. 

350. Hagen : Arch, f ur Schiffs.- u. Trop. Hyg., iv, iii. 

351. Jour. Trop. Med., vol. xi. 

352. Haw : Jour. Trop. Med., Oct. 16, 1899. 

353. Laveran : Bull, de TAcad. de Med., lxix, 32. 

354. Gorgas : Jour. Am. Med. Assoc, 46, 1417. 

355. Annual Reports, U. S. P. H. and M. H. S., 1905-07. 

356. Medizinal Berichte iiber die Deutsch, Schutzgeb., 1903-06. 

357. Parry : Am. Jour. Med. Sci., vii, 339. 

359. Cited by Cardamatis (287). 

360. Cited by Wood : Practical Medicine, Phila., 1847. 

361. Charity Hosp. Reports, New Orleans, 1906-07. 

362. Cited by Cardamatis (363). 

363. Cardamatis : Bull, de la Soc. de Med. de Gand., Nov., 1900. 

364. Cited by Cardamatis (365). 

365. Cardamatis : Bull, de la Soc. de Med. de Gand., Oct., 1900. 

366. Jenkins : Trans. Ark. Med. Soc, 1904, 203. 

367. Cited by Sambon (9). 

368. Michel: N. O. Jour, of Med., 1869. 

369. Malone : Trans. Ark. Med. Soc, 1880, v, 74. 

370. Coste: Rev. in La Presse Med., Sept. 12, 1906. 

371. Steggall : Med. Record, 56, 259. 

372. Austin: Brit. Med. Jour., Feb. 10, 1900. 

373- Cited by Cardamatis, F. B. : Hemoglobinurique, Syra, 1901. 

374- McDaniel : Med. News, Nov. 24, 1883. 

375- Henric: Arch, de Med. Nav., May, 1898. 
376. Kohlstock: Deut. Med. Woch., Nov. 14, 1895. 
377- Ensor: Arch, fur Schiffs.- u. Trop. Hyg., 108. 
378. Cited by F. Plehn (6). 



REFERENCES 395 

379. Cited by Hopkins (260). 

380. Cited by Prentice : Brit. Med. Jour., Sept. 24, 1898. 

381. Dempwolff : Arch, fur Schiffs.- u. Trop. Hyg., June, 1899. 

382. Cited by Hare : Ther. Gaz., July 15, 1892. 

383. Cited by Lewis (192). 

384. Forde : Jour. Trop. Med., Feb. 1, 1908. 

385. Cardamatis : Fievre Bilieuse Hemoglobinurique, Syra, 1901. 

386. Prout : Brit. Med. Jour., Nov. 9, 1907. 

387. Jacobs : New York Med. Jour., Oct. 12, 1907. 

388. DeCruz : Indian Med. Gaz., Nov., 1907. 

389. DeBlasi : Gazef?. degli Osped., April 26, 1903. 

390. Orme : Jour. Trop. Med., xi, 38. 

391. Thompstone: Jour. Trop. Med., xi, 14. 

392. Ross : Mosquito Brigades, New York, 1902. 

393. Rosenau : Disinfection Against Mosquitoes, etc., Washington, 1901. 

394. Cited by Smart (76). 

395. Babes : Munch. Med. Woch., April 4, 1905. 

396. Duncan : Brit. Med. Jour., Sept. 1, 1900. 

397. Annual Report U. S. P. H. and M. H. S., Washington, 1906. 

398. Sambon and Low : Brit. Med. Jour., Dec. 8, 1900. 

399. Busck : Jour. Trop. Med., xi, 252. 

400. Kleine : Zeitschr. fur Hyg. Inf ek., 38, 1907. 

401. Cited by Giemsa and Schaumann (300). 

402. Schmitz : Arch, f iir Exp. Path. u. Pharm., 1907. 

403. Craig : Am. Med., April and May, 1906. 

404. Mannaberg: Die Malaria Parasiten, Vienna, 1893. 

405. Gudden : Arch, fur Schiffs.- u. Trop. Hyg., 1905, 500. 

406. A. Plehn : Arch, f iir Schiffs.- u. Trop. Hyg., ii, 4. 

407. Grenier : Indian Med. Gaz., Feb., 1898. 

408. Quill : Rev. in Med. News, Dec. 5, 1903. 

409. Goodman : Med. Record, 70, 865. 

410. Cited by Tomaselli (205). 

411. Moore: The Lancet, 1863, 660. 

412. Cited by Mauviez : Le Paludisme a Diego-Suarez, Paris, 1905. 

413. Bartholow : Materia Medica, New York, 1894. 

414. Cited by McCampbell (415). 

415. McCampbell : Jour. Am. Med. Assoc, 48, 920. 

416. Bliimchen : Deut. Med. Woch., 1901, No. 17. 

417. Manson : Lectures on Tropical Diseases, Chicago, 1905. 

418. Cited by McElroy (214). 

419. Gros : Bull, de la Soc. de Med. de Gand, Oct., 1900. 

420. Shoemaker : Med. Record, Oct. 29, 1904. 

421. Cited by Vande'rhoof : Jour. Am. Med. Assoc, 48, 1333. 

422. Bacelli: Gaz. degli. Osped., Feb., 1890; Riform. Med., 1890, 6. 

423. Guiterrez : Rev. in Jour. Am. Med. Assoc, Nov. 22, 1902. 

424. Fleury: Jour. Am. Med. Assoc, Dec. 24, 1904. 

425. Holmes : Medical Essays, Boston, 1895. 

426. Demarchi : Policlinico, 1906, xiii, 6. 

427. Brachio : Indian Med. Gaz., March, 1908. 

428. Bell : The Military Surgeon, August, 1907. 

429. Goltman: Memphis Med. Monthly, Nov., 1905. 

430. Guttman and Ehrlich : Berlin Klin. Woch., 1891, 39. 

431. Wood: Med. News, March 4, 1905. 

432. De Blasi : Gaz. degli Ospedali, March 23, 1902. 

433. Thayer : Bull. Johns Hopkins Hosp., May, 1892. 

434. Moore and Allison: Med. News, Dec. 6, 1902. 

435. Grosch : Med. Klinik., 1907, 20. 

436. Wiener : Klin. Woch., June 4, 1908. 

437. Vassal : Le Caduccee, ninth year, 9. 

438. Duncan: Jour. Trop. Med., Oct. 16, 1899. 

439. Carpenter : Med. Record, 70, 165. 



396 THE STUDY OF MALARIA 

440. Quennec : Arch, f iir Schiffs.- u. Trop. Hyg., iii, 2. 

441. Vincent : Compt. Rend. Soc. Biol., Dec. 15, 1905. 

442. Polli : Brit. Med. Jour., Nov. 16, 1867. 

443. O'Sullivan-Beare : The Lancet, Feb. 1, 1902. 

444. Werner: Deut. Med. Woch., 1902, 42. 

445. Cited by Werner: Die Nieren beim Schwarzwasserfieber, Leipzig, 

1907. 

446. Kiilz : Arch, f iir Schiffs.- u. Trop. Hyg., xi, 508. 

447. Cited by Ed. Jour. Am. Med. Assoc, June 24, 1905. 

448. Below : Berl. Klin. Woch., Nov. 15, 1897. 

449. McKay: Glasgow Med. Jour., March, 1908. 



INDEX 



Abdominal forms, 212 

Abortion, 242 

Abscess of liver, diagnosis, 284 

of spleen, 240 
Absorption of quinine, 335 
Action of quinine on parasites, 341 
Acute malaria, 184 
Administration of quinine, 357 
Adult mosquitoes, 81 
Aedeomyia, 100 
Aedes, 93 
Age, 55, 253 

and hemoglobinuric fever, 155 

and immunity, 53 

and pernicious malaria, 141 
Agglutinin, 199 
Albuminuria, 201 
Algid form, 212 
Alkaloids of cinchona, 343 
Altitude, 45 

and hemoglobinuric fever, 158 

and mosquitoes, 104 
Amaurosis, 210 
Amblyopia, diagnosis, 289 
Anemia, pathogenesis, 140 
Anopheles, 88 

breeding places of, 75 

crucians, description, 86 

maculipennis, description, 84 

mosquitoes, 74 

punctipennis, description, 85 
Anophelinse, 87 
Anopheline larvae, 77 

ova, 76 
Apoplectic form, 208 
Apparent death, 207 
Appendicitis, 215 
Ardent form, 210 
Ataxic form, 210 



Bacillus malarias, 20 
Banti's disease, diagnosis, 287 
Beans and hemoglobinuria, 168 
Bilious form, 215 

remittent fever, and hemoglobin- 
uria, 27 
diagnosis, 291 
Biology of parasites, 113 
Biting of mosquitoes, 105 
Blackwater fever. See Hemoglobinuric 

fever. 
Blood, 195, 216, 223 

complications, 236 

examination, 258 
Bone-marrow, pathology, 177, 180, 183 
Brain, pathology, 177, 183 
Breeding mosquitoes, 109 

places, 75 
Bulbar symptoms, 208 

Cachexia, 237 

productive of immunity, 54 

treatment, 369 
Cacomyia, 10 1 
Cancer, complication, 251 
Cardialgic form, 214 
Cellia, 89 

Cerebellar symptoms, 208 
Cerebrospinal forms, 204 
Change of residence, 53, 60 

and hemoglobinuric fever, 158 
and pernicious malaria, 143 

of type, 139, 188 
Children, malaria in, 55, 56, 253 

pernicious malaria in, 141 

treatment, 371 
Chill, description, 184 
Choice of preparation, 356 
Choleraic form, 214 

397 



398 



INDEX 



Chronic malaria, 228 

treatment, 368 
Cinchona, history, 28 
Circulatory system, complications, 232 

symptoms, 195 
Civilization, 61 
Classification of mosquitoes, 86 

of parasites, 112 

of pernicious malaria, 203 
Clearing of land, 48 
Climate, 38 
Clinical history, 184 
Colon bacillus, 252 
Colors and mosquitoes, 106 
Comatose malaria, 204 
Complications, 232 

of hemoglobinuric fever, 226 

treatment, 372 
Congenital immunity, 54 

malaria, 64 
Contra-indications to quinine, 355 
Convulsive form, 209 
Coquillettidia, 100 
Crescents, 231 

pyrogenic properties, 147 
Culex, 98 
Culicella, 97 
Culicinae, 87, 90 
Culiseta, 98 

Cultivation experiments, 129 
Cycles of the parasites, 114 
Cycloleppteron, 89 

Deinocerites, 101 
Deinoceritinse, 87, 101 
Dendromyia, 103 
Destruction of mosquitoes, 305 

of parasites, 315 
Diabetes, complication, 251 
Diagnosis, 256 

differential, 284 

of hemoglobinuric fever, 289 

of pernicious malaria, 287 
Diaphoretic form, 214 
Differential diagnosis, 284 
Disappearance of malaria, 73 
Dissection of mosquitoes, no 
Dissemination by mosquitoes, 69 
Dosage of quinine, 365 
Drinking-water, 62 



Duration of larval stage, 79 
Dysenteric form, 214 

Ear complications, 248 
Earthquakes, 46 
Eclamptic form, 209 
Education and prophylaxis, 327 
Eggs of mosquitoes, 76, 107 
Elimination of quinine, 335 
Endemic index, 56 
Endocarditis, diagnosis, 284 
Endogenous cycle, 114 
Epidemics, 63 

of hemoglobinuric fever, 37 
Error, sources of, 268 
Estivo-autumnal infection, symptoms, 
190 

parasites, 119 

differentiation, 121 
Etiology, 38 

of hemoglobinuric fever, 153 

of pernicious malaria, 140 
Europeans and hemoglobinuric fever, 29 
Examination of blood, 258 
Exclusion of mosquitoes, 322 
Exflagellation, 117 
Exogenous cycle, 123 
Exposure, 60 

to wind, 49 
External etiologic influences, 151 
Eye complications, 248 

Family predisposition and hemoglo- 
binuria, 156 

Feeding of mosquitoes, 70, no 

Females, susceptibility of, 54 

Fertilization of mosquitoes, 70, 107 

Fish and prophylaxis, 311 

Flagella, 117, 268 

Flight of mosquitoes, 105 

Food in etiology, 61 
of mosquitoes, 70, 104 

Gametes, differentiation, 117, 122 

estivo-autumnal, 120 

quartan, 119 

tertian, 117 
Gastralgic form, 214 
Gastro-intestinal organs, complications, 

235 



INDEX 



399 



Gastro-intestinal organs, symptoms, 200 
Genito-urinary organs, complications, 
240 

symptoms, 200 
Geographic distribution, 31 

of hemoglobinuric fever, 34 
Glossary of terms, 128 
Grabhamia, 97 
Ground water, 43, 308 
Gymnometopa, 101 

Habits of mosquitoes, 104 
Haemamceba immaculata, 119 
malarias, 118 
parva, 119 
praecox, 119 
quartanae, 118 
tertianae, 115 
vivax, 115 
Haematozoon falciform, 120 
Haemocytozoa, 112 
Haemogogus, 101 
Haemomenas praecox, 119 
Hayem's method, 259 
Heart, pathology, 177, 180, 183 
Hematuria. See Hemoglobinuric jever. 
Hemiplegia, 209 

Hemoglobinuric fever, complications, 
226 
diagnosis, 289 
etiology, 153 

geographic distribution, 34 
history, 23 
pathogenesis, 160 
pathology, 180 
prognosis, 297 
prophylaxis, 332 
quinine and, 26 
sequelae, 226 
symptoms, 216 
treatment, 380 
Hemolysin, 199 
Hemosiderin, 174 
Hibernation of larvae, 107 
mosquitoes, 108 
ova, 107 
parasites, 71 
pupae, 108 
History of cinchona, 28 
of hemoglobinuric fever, 23 



History of malaria, 18 
Howardina, 101 
Human cycle, 114 
Hydrophobic form, 209 
Hygienic treatment, 365 
Hypodermic method, 359 

Idiosyncrasy, 156 
Imago of mosquitoes, 81 
Immunity, 50 

congenital, 54 
Incubation, 184 
Index endemicus, 56 
Individual predisposition, 151 
Infection, modes of, 63 
Influenza, complication, 251 

diagnosis, 286 
Inheritance of parasites by mosquitoes, 

7i 
Inoculation, 67 
Insecticides, 312 

Intestines, pathology, 176, 180, 182 
Intravenous method, 363 
Introduction, 17 
Inundations, 47, 143 
Isolation of patients, 327 
Isostomyia, 99 

Janthinosoma, 92 

Key to mosquitoes, 86 

Kidneys, pathology, 176, 179, 182 

Killing mosquitoes, 108 

Larv^S, differentiation, 79 

hibernation, 107 
Larval stage, duration, 79 
Latent malaria, 228 

pathogenesis, 139 
Laverania malariae, 118 

praecox, 119 
Leishman's stain, 262 
Length of flight of mosquitoes, 105 

of life of mosquitoes, 107 

of residence, 59, 143, 157 
Lepidoplatys, 93 
Lepidosia, 92 
Leukemia, diagnosis, 287 
Leukocytes, 197, 223, 279 
Life of mosquitoes, length, 107 



400 



INDEX 



Limatus, 103 

Liver, pathology, 175, 178, 181 
Localizations of parasites, 150 
Lungs, pathology, 176, 180, 183 
Lutzia, 97 

Malaria upon ships, 49 

without mosquitoes, 72 
Malaria-bearing mosquitoes, 74 
Malarial parasites, 112 
Malignant tertian, 191 
Marshes, 43 
Masked malaria, 232 
Megarhinae, 87, 89 
Megarhinus, 89 
Melanin, 174 
Melanoconion, 99 
Methods of administration, 357 
Methylene-blue, 373 
Micraedes, 99 

Microscopic examination of blood, 258 
Midgut, dissection, no 
Mixed infections, 193 
Modes of infection, 63 
Mononuclear increase, 279 
Mortality, 295 

of hemoglobinuric fever, 298 

of pernicious malaria, 296 
Mounting mosquitoes, 109 
Mythology and malaria, 18 
Myzomyia, 88 
Mosquito cycle, 123 

larvae, 77 

pups, 80 
Mosquitoes as malaria carriers, 22 

classification, 86 

description of adult, 81 

destruction of, 305 

hemoglobinuric fever and, 36 

hibernation of, 108 

list of malaria-bearing, 74 

malaria-bearing, 69 

Negative results, 277 

Negro, 141, 253 

Nephritis, 240 

Nervous system, complications, 243 

symptoms, 202 
Nobel prizes, 18 



Nocht-Romanowsky stain, 262 
Notes of mosquitoes, 105 
Nototricha, 89 
Number of parasites, 147 

Objections to mosquito theory, 72 
Occasional causes of hemoglobinuria, 

159 
Occupation, 60, 143, 159 
Ochlerotatus, 93 
Odors and mosquitoes, 106 
Opium-eating and immunity, 62 
Ova, hibernation, 107 

of anopheles, 76 

of mosquitoes, 107 
Overflows, 47, 143 
Oviposition of mosquitoes, 107 

Palmate hairs of larvae, 78 
Parasites, biology, 113 

classification, 112 

estivo-autumnal, 119 

in hemoglobinuric fever, 161 

localizations, 150 

number, 150 

quartan, 118 

table of differentiation, 122 

tertian, 115 
Paroxysm, description, 184 
Parthenogametes, 126 
Parthenogenesis, 139, 229 

in mosquitoes, 107 
Parthenogenetic cycle, 114, 124 
Pathogenesis, 129 

of hemoglobinuric fever, 160 

of pernicious malaria, 145 
Pathology, 174 

of hemoglobinuric fever, 180 
Pericardium, pathology, 183 
Periodicity, 256 
Peritonitis, 215 

Pernicious malaria, diagnosis, 287 
etiology, 140 
prognosis, 295 
symptoms, 203 
treatment, 378 
Perpetuation of parasites, 71 
Petroleum in prophylaxis, 309 
Phagocytosis, 224 



INDEX 



40I 



Phoniomyia, 103 

Physiologic effects of quinine, 349 

Pigment, 278 

Plants and malaria, 48 

Plasmodium falciparum, 120 

immaculatum, 119 

malariae, 118 

prascox, 119 

vivax, 115 
Pleurae, pathology, 183 
Pneumaculex, 101 
Pneumonic form, 211 
Positive results, 275 
Postmalarial fever, 194 
Pregnancy, 55, 242 

and quinine, 353 
Previous attacks of hemoglobinuric fever, 
156 

of malaria, 144 
Private prophylaxis, 332 
Prodromata, 185 
Prognosis, 292 

of hemoglobinuric fever, 297 

of pernicious malaria, 295 
Prophylaxis, 302 

of hemoglobinuric fever, 332 
Psorophora, 90 
Psorophorinae, 87, 90 
Puerperal septicemia, diagnosis, 285 
Puerperium, 55 
Pupae, 80 

differentiation, 80 

hibernation, 108 

Quartan infection, symptoms, 189 

parasite, 118 
Quinine, 334 

absorption and elimination, 335 

action on parasites, 341 

and pregnancy, 353 

contra-indications, 355 

effect on parasites, 271 

in etiology of hemoglobinuric fever, 26, 
164 

methods of administration, 357 

physiologic effects, 349 

prophylaxis, 316 

substitutes, 372 

test, 281 
Quotidian estivo-autumnal, 192 

26 



Race, 50, 253 

and hemoglobinuric fever, 154 

and pernicious malaria, 141 
Rainfall, 41 

Rectal administration, 364 
Relapse, 228 

in pernicious malaria, 207 

pathogenesis, 139 
Residence, change of, 143, 158 

length of, 59, 143, 157 
Respiratory system, complications, 233 

symptoms, 199 
Resting position of larvae, 79 

of mosquitoes, 84 
Rice culture, 60 
Ring forms, differentiation, 123 
Romanowsky stain, 261 
Rupture of spleen, 239 

Sabethes, 103 
Sabethoides, 103 
Salivary glands, dissection, in 
Salt marshes, 45 

water and mosquitoes, 75 
Schizogonic cycle, 114 
Schiiffner's dots, 197 
Screens, 322 
Season, 39 

and hemoglobinuric fever, 156 

and mosquitoes, 103 

and pernicious malaria, 142 
Secondary fever, 194 
Sequelae, 232 

of hemoglobinuric fever, 226 
Sex, 54 

and hemoglobinuric fever, 155 

and pernicious malaria, 141 
Ships, malaria on, 49 
Sitting position of mosquitoes, 84 
Skin complications, 248 

symptoms, 202 
Smallpox, complication, 252 
Social condition, 61, 144 
Soil, 42 

Solubility of quinine salts, 334 
Sources of error, 268 
Spleen, abscess of, 240 

pathology, 175, 178, 181 

rate, 58 

rupture of, 239 



402 



INDEX 



Splenic enlargement, pathogenesis, 140 
Spodogenous fever, 194 
Spontaneous recovery, 292 

pathogenesis, 140 
Sporogonic cycle, 123 
Stegomyia, 93 
Stippling, 196 

Stomach, pathology, 176, 180, 182 
Study of mosquitoes, 108 
Substitutes for quinine, 372 
Sudoral form, 214 
Surgical aspect, 254 
Swamps, 43 
Symptoms, 184 

analysis, 193 

of hemoglobinuric fever, 216 

of pernicious malaria, 203 
Symptomatic treatment, 367 
Syncopal form, 214 
Syphilis, complication, 252 

T^NIORRHYNCHUS, IOO 

Technic of blood examination, 258 

of mosquito study, 108 
Temperature, atmospheric, 38 

and mosquitoes, 103 

clinical, 193, 218 
Tertian estivo-autumnal, 191 

infection, symptoms, 187 

parasite, 115 
Tetanic form, 209 
Texas fever, 162 
Theobaldia, 98 
Therapeutic test, 281 
Thick film process, 268 
Thoracic forms, 211 
Time of administration, 365 
Tinolestes, 99 
Topography, 43 



Toxin, 130, 151 

in hemoglobinuric fever, 163 
Treatment, 334 

of hemoglobinuric fever, 380 

of pernicious malaria, 378 
Trees, effect on malaria, 48 

in prophylaxis, 309 
Trichoprosopon, 102 
Trichoprosoponinae, 87, 102 
Tuberculosis, complication, 251 

diagnosis, 286 
Typhoid fever, complication, 250 
diagnosis, 285 
form, 210 

Uninhabited regions, malaria in, 74 
Unity of the malarial parasites, 113 
Uranotaenia, 102 
Uranotamiina;, 87, 102 
Urine, 200, 219 

Vegetation, 48 
Verrallina, 93 
Volcanic eruptions, 46 

Water, contagion through, 62 
Weeds and malaria, 48 
Wind, malaria borne by, 48 
mosquitoes borne by, 106 
Wings of mosquitoes, 83 
Wright's stain, 263 
Wyeomyia, 103 

Yellow fever and hemoglobinuric fever, 
28 
diagnosis, 291 

Zoologic relations of the parasites, 
112 



SAUNDERS* BOOKS 

• — orv — 

SURGERY 



and 



ANATOMY 



W. B. SAUNDERS COMPANY 

925 WALNUT STREET PHILADELPHIA 

9, HENRIETTA STREET COVENT GARDEN, LONDON 



SAUNDERS* REMARKABLE SUCCESS 

\ATE are often asked to account for our extraordinary success. 
* * We can but point to modern business methods, carefully per- 
fected business machinery, and unrivalled facilities for distribution of 
books. Every department is so organized that the greatest possible 
amount of work is produced with the least waste of energy. The 
representatives of the firm are men with life-long experience in the 
sale of medical books. Then, too, we must not overlook that major 
force in the modern business world — advertising. We have a special 
department devoted entirely to the planning, writing, and placing of 
advertising matter ; and we might mention that the money annually 
spent in advertising now far exceeds the entire annual receipts of the 
House during its earlier years. These extraordinary facilities for dis- 
posing of large editions enable us to devote a large amount of money 
to the perfecting of every detail in the manufacture of books. 

A Complete Catalogue of our Publications will be Sent upon Request 



SAUNDERS' BOOKS O IV 



KeenV Surgery 

AN UNABRIDGED TREATISE FOR THE SURGEON AND 
THE GENERAL PRACTITIONER 



Surgery : Its Principles and Practice. Written by 66 eminent 
specialists. Edited by W. W. Keen, M.D., LL.D., Hon. F.R.C.S., Eng. 
and Edin., Emeritus Professor of the Principles of Surgery and of 
Clinical Surgery at the Jefferson Medical College. Five octavos of IOOO 
pages each, containing 2500 text-illustrations and 50 colored plates. 
Per volume : Cloth, $7.00 net ; Half Morocco, $8.00 net. 

IN FIVE VOLUMES— 2500 TEXT-CUTS AND 50 COLORED PLATES 
THE FIFTH AND LAST VOLUME NOW READY 

THE EMINENT CONTRIBUTORS 



Robert Abbe, M.D. 
J. G. Adami, M.D. 
E. Wyllys Andrews, M.D. 
G. E. Armstrong, M.D. 
A. D. Bevan, M.D. 
Warren S. Bickham, M.D. 
John F. Binnie, M.D. 
P. Brooke Bland, M.D. 
George E. Brewer, M.D. 
J. Bland-Sutton, F.R.C.S. 
A. T. Cabot, M.D. 
Hampton L. Carson, Esq. 
E. A. Codman, M.D. 
Wm. B. Coley, M.D. 
W. M. L. Coplin, M.D. 
George W. Crile, M.D. 
Harvey Cushing, M.D. 
J. Chalmers DaCosta, M.D. 
John C. DaCosta, Jr., M.D. 

E. B. Dench, M.D. 

F. X. Dercum, M.D. 

G. E. deSchweinitz, M. D. 
David L. Edsall, M. D. 



D. N. Eisendrath, M.D. 
Wm. L. Estes, M.D. 
J. M. T. Finney, M.D. 
John M. Fisher, M.D. 
John A. Fordyce, M.D. 
Chas. H. Frazier, M.D. 
Leonard Freeman, M.D. 
Frederick H. Gerrish, M.D. 
John H. Gibbon, M.D. 
Georg Gottstein, M. D. 
Hobart A. Hare, M. D. 
Ludvig Hektoen, M.D. 
Orville Horwitz, M.D. 
Allen B. Kanavel, M.D. 
Albert Kocher, M.D. 
Karl Gustav Lennander, M.D. 
Bransford Lewis, M.D. 
R. W. Lovett, M.D. 
Edward Martin, M.D. 
Rudolph Matas, M.D. 
Chas. A. Mayo, M.D. 
W T m. J. Mayo, M.D. 
Maj. Walter D. McCaw, M.D. 



E. E. Montgomery, M.D. 
B. G. A. Moynihan, F.R.C.S. 
J. G. Mumford, M.D. 
John C. Munro, M.D. 
John B. Murphy, M.D. 

E. H. Nichols, M.D. 
A. J. Ochsner, M.D. 
Surg.-Gen.R.M.O' Reilly.U.S.A. 
Edmund Owen, F.R.C.S. 

Jos. Ransohoff, M.D. , F.R.C.S. 
Surg.-Gen. R M. Rixey,U.S.N. 
John B. Roberts, M.D. 
A. W. Mayo Robson, F.R.C.S 
W. L. Rodman, M.D. 
Eugene A. Smith, M.D. 
Harmon Smith, M.D. 
Wm. G. Spiller, M.D. 
Weller Van Hook, M.D. 
J. P. Warbasse, M.D. 

F. C. Wood, M.D. 
George Woolsey, M.D. 
Hugh H. Young, M.D. 
Fredrik Zachrisson, M.D. 



SURGER Y AND ANA TOMY 



Kelly and Noble's 
Gynecology 
and Abdominal Surgery 



Gynecology and Abdominal Surgery. Edited by Howard A. 
Kelly, M. D., Professor of Gynecology in Johns Hopkins University ; 
and Charles P. Noble, M. D., Clinical Professor of Gynecology in the 
Woman's Medical College, Philadelphia. Two imperial octavo volumes 
of 950 pages each, containing 880 original illustrations, some in colors. 
Per volume : Cloth, $8.oo net; Half Morocco, $9.50 net. 

BOTH VOLUMES NOW READY 

WITH 880 ILLUSTRATIONS BY HERMANN BECKER AND MAX BRODEL 

In view of the intimate association of gynecology with abdominal surgery the 
editors have combined these two important subjects in one work. For this reason 
the work will be doubly valuable, for not only the gynecologist and general prac- 
titioner will find it an exhaustive treatise, but the surgeon also will find here the 
latest technic of the various abdominal operations. It possesses a number of 
valuable features not to be found in any other publication covering the same fields. 
It contains a chapter upon the bacteriology and one upon the pathology of gyne- 
cology, dealing fully with the scientific basis of gynecology. In no other work 
can this information, prepared by specialists, be found as separate chapters. 
There is a large chapter devoted entirely to medical gynecology, written especially 
for the physician engaged in general practice. Heretofore the general practi- 
tioner was compelled to search through an entire work in order to obtain the in- 
formation desired. Abdominal surgery proper, as distinct from gynecology, is 
fully treated, embracing operations upon the stomach, upon the intestines, upon 
the liver and bile-ducts, upon the pancreas and spleen, upon the kidneys, ureter, 
bladder, and the peritoneum. The illustrations are truly magnificent, being the 
work of Mr. Hermann Becker and Mr. Max Brodel. 

American Journal of the Medical Sciences 

" It is needless to say that the work has been thoroughly done ; the names of the authors 
and editors would guarantee this, but much may be said in praise of the method of presentation, 
and attention may be called to the inclusion of matter not to be found elsewhere." 



SAUNDERS' BOOKS ON 



Cotton's 

Dislocations and Joint Fractures 

Dislocations and Joint Fractures. By Frederic Jay Cotton, M. D-, 
Associate Professor of Clinical Surgery at Tuft's Medical School, Boston. 
Octavo volume of 600 pages, with 850 original illustrations. 

PREPARING— ORIGINAL ILLUSTRATIONS 

Dr. Cotton's clinical and teaching experience in this field has especially fitted 
him to write a practical work on this subject. He has written a book clear and 
definite in style, systematic in presentation, and accurate in statement. The 
illustrations possess the feature of showing just those points the author wishes to 
emphasize. This is made possible because the author is himself the artist, by 
far the greater majority of the illustrations being the work of his own hand. 
They are strikingly artistic as well as unusually practical. 

Kemp on Gastro- 
intestinal Diseases 

Diagnosis and Treatment of Gastrointestinal Diseases. By Rob- 
ert Coleman Kemp, M. D., Professor of Gastro-intestinal Diseases at 
the New York School of Clinical Medicine. Octavo of 750 pages, with 
250 original illustrations. 

PREPARING— ELABORATELY ILLUSTRATED 

Of the many works on gastro-intestinal diseases, this is perhaps the only one 
in which the needs of the general practitioner are given pre-eminent emphasis. 
It is the practitioner who first meets with these cases, and it is he upon whom the 
burden of diagnosis rests. After the diagnosis is established, the practitioner, if 
properly equipped, could frequently treat the case himself instead of transferring 
it to a specialist. This work is intended to equip the practitioner with this end in 
view. As visceral displacements have assumed such an important position, their 
symptoms, diagnosis, and treatment, notably by mechanical methods, are specially 
described. Typhoid fever is also included because of its local manifestations. A 
chapter is devoted to diverticulitis, now a subject of much importance. The illus- 
trations, all original, represent photographs of actual cases. 



SURGERY AND ANATOMY 



Fowler's 
Treatise on Surgery 

A Treatise on Surgery. By George R. Fowler, M. D., Emeritus 
Professor of Surgery, New York Polyclinic. Two imperial octavos of 
725 pages each, with 888 original text-illustrations and 4 colored 
plates. Per set : Cloth, $15.00 net ; Half Morocco, $18.00 net. 

IN TWO VOLUMES 

Without doubt, Dr. Fowler's work is the most practical and complete surgery 
for its size ever published. Every sentence tells its story, either to recount a fact 
or give instruction as to treatment. The author especially emphasizes those 
injuries and surgical diseases that are of the greatest importance, not only because 
of their frequency, but also because of the difficulty of diagnosis and the special 
care demanded in their treatment. The text is elaborately illustrated with 888 
entirely new and original illustrations, and every picture actually shows some 
surgical procedure, some step in the technic of an operation ; every picture indi- 
cates precisely how to do something. 

JRudoph Mat&s, M. D., Professor of Surgery, Tulane University of Louisiana. 

" After a careful examination of this work I am glad to state that the completed text fully 
confirms the assurance I entertained : that this would prove a work of high order and dis- 
tinct merit. These splendid volumes fully justify the repute of their author for earnestness, 
thoroughness, and learning." . 

Gant on Constipation and 
Intestinal Obstruction 

Constipation and Intestinal Obstruction. By Samuel G. Gant, 
M. D., Professor of Diseases of the Rectum and Anus, New York 
Post-Graduate Medical School and Hospital. Octavo of 559 pages, 
with 250 original illustrations. Cloth, $6.00 net ; Half Morocco, $7.50 net. 

RECENTLY ISSUED— INCLUDING RECTUM AND ANUS 

In this work the consideration given to the medical treatment of constipation 
is unusually extensive. The practitioner will find of great assistance the chapter 
devoted to formulas. The descriptions of the operative procedures are concise, 
yet fully explicit. 

The Proctologist 

"Were the profession better posted on the contents of this book there would 
be less suffering from the ill effects of constipation. We congratulate the author 
on this most complete book." 



SAUNDERS' BOOKS ON 



Bier's 
Hyperemic Treatment 

By WILLY MEYER, M. D., and Prof. V. SCHMIEDEN 



Bier's Hyperemic Treatment in Surgery, Medicine, and the Special- 
ties : A Manual of its Practical Application. By Willy Meyer, M. D., 
Professor of Surgery at the New York Post-Graduate Medical School 
and Hospital ; and Prof. Dr. Victor Schmieden, Assistant to Prof. 
Bier, University of Berlin, Germany. Octavo of 280 pages, with 
original illustrations. Cloth, $3.00 net. 

JUST READY— THE NEW (2d) EDITION— FOR THE PRACTITIONER 

For the practitioner this work has a particular value, because it gives special 
attention to the hyperemic treatment of those conditions with which he comes in 
daily contact. Yet the needs of the surgeon and the specialist have not, by any 
means, been neglected. The work is not a translation, but an entirely original 
book, by Dr. Willy Meyer, who has practised the treatment for the past fifteen 
years, and Prof. Schmieden, Professor Bier's assistant at Berlin University. In 
the first part the three methods of inducing hyperemia are described; in the second, 
are taken up the details of application. 

New York State Journal of Medicine 

" We commend this work to all those who are interested in the treatment of infections, 
either acute or chronic, for it is the only authoritative treatise we have in the English language." 



Campbell's Surgical Anatomy 

A Text=Book of Surgical Anatomy. By William Francis Camp- 
bell, M. D., Professor of Anatomy, Long Island College Hospital. 
Octavo of 675 pages, with 319 original illustrations. Cloth, $5.00 net; 
Half Morocco, $6.50 net. 

WITH 319 PRACTICAL ILLUSTRATIONS 

The first aim in the preparation of this original work was to emphasize the 
practical. It is in the fullest sense an applied anatomy — -an anatomy that will be 
of inestimable value to the surgeon because only those facts are discussed and 
only those structures and regions emphasized that have a peculiar interest to him. 
Dr. Campbell has treated his subject in a very systematic way. The magnificent 
original illustrations will be found extremely practical. 

Boston Medical and Surgical Journal 

"The author has an excellent command of his subject, and treats it with the freedom and 
the conviction of the experienced anatomist. He is also an admirable clinician." 



SURGER Y AND ANA TO MY 



$c\idder*s 
Treatment of Fractures 

WITH NOTES ON DISLOCATIONS 

The Treatment of Fractures : with Notes on a few Common 
Dislocations. By Charles L. Scudder, M. D., Surgeon to the Massa- 
chusetts General Hospital, Boston. Octavo of 628 pages, with 854 
original illustrations. Polished Buckram, $5.50 net; Half Morocco, 
$7.00 net. 

THE NEW (6th) EDITION, REVISED AND ENLARGED 
OVER 26,500 COPIES 

The fact that this work has attained a sixth edition indicates its practical 
value. In this edition Dr. Scudder has made numerous additions throughout 
the text, and has added many new illustrations, greatly enhancing the value of 
the work. The articles on Dislocations, illustrated in that practical manner 
which has made Dr. Scudder' s work so useful, will be found extremely val- 
uable. 

Joseph D. Bryant, M.D., Professor of the Principles and Practice of Surgery, University 

and Bellevue Hospital Medical College. 

"As a practical demonstration of the topic it is excellent, and as an example of bookmaking 
it is highly commendable." 



Bickham's Operative Surgery 

A Text=Book of Operative Surgery. By Warren Stone Bickham, 
M. D., Phar. M., of New Orleans. Octavo of 1200 pages, with 854 
original illustrations. Cloth, $6.50 net ; Half Morocco, $8.00 net. 

THE NEW (3d) EDITION 

This absolutely new work completely covers the surgical anatomy and opera- 
tive technic involved in the operations of general surgery. The practicability of 
the work is particularly emphasized in the 854 magnificent illustrations which form 
a useful and striking feature. 

Boston Medical and Surgical Journal 

" The book is a valuable contribution to the literature of operative surgery. It represents 
a vast amount of careful work and technical knowledge on the part of the author. For the sur- 
geon in active practice or the instructor of surgery, it is an unusually good review of the subject." 



SAUNDERS' BOOKS ON 



Moynihan*s 
Abdominal Operations 



Abdominal Operations. By B. G A. Moynihan, M. S. (Lond.), 
F.R.C.S., Senior Assistant Surgeon, Leeds General Infirmary, England. 
Octavo, beautifully illustrated. Cloth, $7.00 net ; Half Morocco, $8.50 net. 

THE NEW (2d) EDITION 
TWO LARGE EDITIONS IN ONE YEAR 

It has been said of Mr. Moynihan that in describing details of operations he 
is at his best. The appearance of this, his latest work, therefore, will be widely 
welcomed by the medical profession, giving, as it does, in most clear and exact 
language, not only the actual modus operandi of the various abdominal operations, 
but also the preliminary technic of preparation and sterilization. Complications 
and sequelae and after-treatment are presented in the same clear, clean-cut manner 
as the operations themselves. The beautiful illustrations have been especially drawn. 

Edward Martin, M. D. 

Professor of Clinical Surgery, University of Pennsylvania 

"It is a wonderfully good book. He has achieved complete success in illustrating, both 
by words and pictures, the best technic of the abdominal operations now commonly performed. " 



Moynihan on Gall-stones 



Gall=stones and Their Surgical Treatment. By B. G. A. Moyni- 
han, M. S. (Lond.), F.R.C.S., Senior Assistant Surgeon, Leeds General 
Infirmary, England. Octavo of 458 pages, fully illustrated. Cloth, 
$ 5.00 net; Half Morocco, $6.50 net. 

THE NEW (2d) EDITION 

Mr. Moynihan, in revising his book, has made many additions to the text, so 
as to include the most recent advances. Especial attention has been given to a 
detailed description of the early symptoms in cholelithiasis, enabling a diagnosis 
to be made in the stage in which surgical treatment can be most safely adopted. 
Every phrase of gall-stone disease is dealt with, and is illustrated by a large 
number of clinical records. The account of the operative treatment of all the 
forms and complications of gall-stone disease is full and accurate. A number of 
the illustrations are in color. 

British Medical Journal 

" He expresses his views with admirable clearness, and he supports them by a large num- 
ber of clinical examples, which will be much prized by those who know the difficult problems 
and tasks which gall-stone surgery not infrequently presents." 



SURGER V AND ANA TOM\ 



Schultze and Stewart's 
Topographic Anatomy 

Atlas and Text=Book of Topographic and Applied Anatomy. By 

Prof. Dr. 0. Schultze, of Wiirzburg. Edited, with additions, by 
George D. Stewart, M.D., Professor of Anatomy and Clinical Sur- 
gery, University and Bellevue Hospital Medical College, N. Y. Large 
quarto of 189 pages, with 25 colored figures on 22 colored lithographic 
plates, and 89 text-cuts, 60 in colors. Cloth, $5.50 net. 

WITH BEAUTIFUL COLORED PLATES 

It was Professor Schultze' s special aim, in preparing this work, to produce a 
Text-Book and Atlas, not for the anatomist alone, but more particularly for the 
general practitioner. The value of the knowledge of topographic anatomy in bed- 
side diagnosis is emphasized throughout the book. The many colored lithographic 
plates are exceptionally excellent. 

Arthur Dean Bevan. M. D., Professor of Surgery in Rush Medical College, Chicago. 

" I regard Schultze and Stewart's Topographic and Applied Anatomy as a very admirable 
work, for students especially, and I find the plates and the text excellent." 

Sobotta and McMurrich's 
Human Anatomy 

Atlas and Text=Book of Human Anatomy. In Three Volumes. By 
J. Sobotta, M.D., of Wiirzburg. Edited, with additions, by J. Playfair 
McMurrich, A. M., Ph. D., Professor of Anatomy, University of 
Toronto, Canada. Three large quartos, each containing about 250 
pages of text and over 300 illustrations, mostly in colors. Per volume: 
Cloth, $6.00 net ; Half Morocco, $7.50 net. 

VOLUME III NOW READY— COMPLETING THE WORK 

The great advantage of this over other similar works lies in the large number 
of magnificent lithographic plates which it contains, without question the best that 
have ever been produced in this field. They are accurate and beautiful reproduc- 
tions of the various anatomic parts represented. 
Edward Martin, M.D., Professor of Clinical Surgery, University of Pennsylvania. 

"This is a piece of bookmaking which is truly admirable, with plates and text so well 
chosen and so clear that the work is most useful to the practising surgeon." 



io SAUNDERS' BOOKS ON 



Eisendrath's 
Surgical Diagnosis 

A Text=Book of Surgical Diagnosis. By Daniel N. Eisendrath, 
M.D., Professor of Surgery in the College of Physicians and Surgeons, 
Chicago. Octavo of 800 pages, with 500 entirely new and original 
text-illustrations and some colored plates. Cloth, $6.50 net; Half 
Morocco, $8.00 net. 

JUST ISSUED— THE NEW (2d) EDITION 

Of first importance in every surgical condition is a correct diagnosis, for upon 
this depends the treatment to be pursued ; and the two — diagnosis and treatment — 
constitute the most practical part of practical surgery. Dr. Eisendrath takes up 
each disease and injury amenable to surgical treatment, and sets forth the means 
of correct diagnosis in a systematic and comprehensive way. Definite directions 
as to methods of examination are presented clearly and concisely, providing for 
all contingencies that might arise in any given case. Each illustration indi- 
cates precisely how to diagnose the condition considered. 

Surgery, Gynecology, and Obstetrics 

"The book is one which is well adapted to the uses of the practising surgeon who desires 
information concisely and accurately given. . . . Nothing of diagnostic importance is omitted, 
yet the author does not run into endless detail." 



Eisendrath's Clinical Anatomy 

A Text=Book of Clinical Anatomy. By Daniel N. Eisendrath, 
A.B., M.D., Professor of Surgery in the College of Physicians and 
Surgeons, Chicago. Octavo of 535 pages, illustrated. Cloth, $5.00 
net; Half Morocco, $6.50 net. 

THE NEW (2d) EDITION 

This new anatomy discusses the subject from the clinical standpoint. A por- 
tion of each chapter is devoted to the examination of the living through palpation 
and marking of surface outlines of landmarks, vessels, nerves, thoracic and 
abdominal viscera. The illustrations are from new and original drawings and 
photographs. This edition has been carefully revised. 

Medical Record, New York 

" A special recommendation for the figures is that they are mostly original and were 
made for the purpose in view. The sections of joints and trunks are those of formalinized 
cadavers and are unimpeachable in accuracy." 



SURGER Y AND ANA TOMY 1 1 



Irvterrvational 
Text-Book of Surgery 

SECOND EDITION, THOROVGHLY REVISED AND ENLARGED 

The International Text=Book of Surgery. In two volumes. By 
American and British authors. Edited by J. Collins Warren, M.D., 
LL.D., F.R.C.S. (Hon.), Professor of Surgery, Harvard Medical 
School ; and A. Pearce Gould, M.S., F.R.C.S., of London, England. — 
Vol. I. General and Operative Surgery. Royal octavo, 975 pages, 
461 illustrations, 9 full-page colored plates. — Vol. II. Special or 
Regional Surgery. Royal octavo, 1122 pages, 499 illustrations, and 
8 full-page colored plates. 

Per volume : Cloth, $5.00 net; Half Morocco, $6.50 net. 

American text-book of Surg'ery 

FOURTH EDITION, RECENTLY ISSUED— OVER 43,000 COPIES 

American Text=Book of Surgery. Edited by W. W. Keen, M.D., 
LL.D., Hon. F.R.C.S., Eng. and Edin., and J. William White, M. D., 
Ph.D. Octavo, 1363 pages, 551 text-cuts and 39 colored and half-tone 
plates. Cloth, $7.00 net; Half Morocco, $8.50 net. 

Robson and Cammidge 
on the Pancreas 

The Pancreas : its Surgery and Pathology. By A. W. Mayo Rob- 
son, F. R. C. S., of London, England ; and P. J. Cammidge, F. R. C. S., of 
London, England. Octavo of 546 pages, illustrated. Cloth, $5.00 net ; Half 
Morocco, $6.50 net. 

ILLUSTRATED 

This new work, upon one of the most widely discussed subjects of the times, 
represents the original investigations of these eminent authorities. There are 
special chapters on Chemical Pathology and Diabetes. 

Boston Medical and Surgical Journal 

" For the general practitioner and surgeon it is the most valuable volume on the subject of 
surgical diseases of the pancreas which has been published in English up to this time." 



12 SAUNDERS' BOOKS ON 

Gould's Operations on the 
Intestines and Stomach 

The Technic of Operations upon the Intestines and Stomach. By 

Alfred H. Gould, M. D., of Boston. Large octavo, with 190 original 
illustrations, some in colors. Cloth, $5.00 net; Half Morocco, $6.5onet. 

WITH 190 ORIGINAL ILLUSTRATIONS 

Dr. Gould's new work is the result of exhaustive experimentation, the technic 
of the operations described being simplified as far as possible by experiments on 
animals, thus leading to the development of many new features. The text is pur- 
posely concise, the technic being presented very clearly by the numerous practical 
illustrations, all made from actual operations done either upon the animal or the 
human being. As the success of gastro-intestinal surgery depends upon an accur- 
ate knowledge of the elementary steps, a thorough account of repair is included. 

New York State Journal of Medicine 

" The illustrations are so good that one scarcely needs the text to elucidate the steps of 
the operations described. The work represents the best surgical knowledge and skill." 



DaCosta's Modern Surgery 

Modern Surgery — General and Operative. By John Chalmers 
DaCosta, M. D., Professor of Surgery and of Clinical Surgery in the 
Jefferson Medical College, Philadelphia. Octavo of 1283 pages, with 
872 illustrations. Cloth, $5.50 net; Half Morocco, $7.00 net. 

THE NEW (5th) EDITION 

For this new fifth edition the work has been entirely rewritten and reset. One 
hundred and fifty new illustrations have been added ; and the work has been en- 
larged by the addition of two hundred pages. To keep the book of a size to handle 
conveniently, a thinner but high-grade paper has been used. DaCosta's Surgery 
in this edition will more than maintain the reputation already won. 

Boston Medical and Surgical Journal 

" We commend the book, as we have previously commended it, to surgeons and to students 
as the most satisfactory one-volume contemporaneous treastise on surgery published in this 
country." 



SURGER Y AND ANA TOMY 



Preiswerk and Warren's Dentistry 

Atlas and Epitome of Dentistry. By Prof. G. Preiswerk, of Basil. Ed- 
ited, with additions, by George W. Warren, D.D.S., Professor of Operative 
Dentistry, Pennsylvania College of Dental Surgery, Philadelphia. With 44 
lithographic plates, 152 text-cuts, and 343 pages of text. Cloth, $3.50 net. 
I)i Saunders Atlas Series. 

" Nowhere in dental literature have we ever seen illustrations which can begin to compare 
with the exquisite colored plates produced in this volume." — Dental Review. 

Griffith's Hand-Book of Surgery 

A Manual of Surgery. By Frederic R. Griffith, M. D., Surgeon to the 
Bellevue Dispensary, New York City. i2mo of 579 pages, with 417 illus- 
trations. Flexible leather, $2.00 net. 

" Well adapted to the needs of the student and to the busy practitioner for a hasty review of important 
points in surgery." — American Medicine. 

Keen's Addresses and Other Papers 

Addresses and Other Papers. Delivered by William W. Keen, M. b., 
LL.D., F. R. C. S. (Hon.), Professor of the Principles of Surgery and of Clin- 
ical Surgery, Jefferson Medical College, Philadelphia. Octavo volume of 
441 pages, illustrated. Cloth, $3.75 net 

Keen on th.e Surgery of Typhoid 

The Surgical Complications and Sequels of Typhoid Fever. By Wm. W. 

Keen, M.D., LL.D., F.R.C.S. (Hon.), Professor of the Principles of Surgery 
and of Clinical Surgery, Jefferson Medical College, Philadelphia, etc 
Octavo volume of 386 pages, illustrated. Cloth, $3.00 net. 

" Every surgical incident which can occur during or after typhoid fever is amply discussed and fully 
illustrated by cases. . . . The book will be useful both to the surgeon and physician." — The 
Practitioner, London. 

Lewis' Anatomy and Physiology for Nurses 

Anatomy and Physiology for Nurses. By LeRoy Lewis, M. D., Surgeon 
to and Lecturer on Anatomy and Physiology for Nurses at the Lewis Hospital, 
Bay City, Michigan. i2mo, 347 pages, with 146 illustrations. Cloth, #1.75 net. 

A demand for such a work as this, treating the subjects from the nurse ' s point of view, has 
long existed. Dr. Lewis has based the plan and scope of this work on the methods em- 
ployed by him in teaching these branches, making the text unusually simple and clear. 
" It is not in any sense rudimentary, but comprehensive in its treatment of the subjects in hand." — 
Nurses Journal of the Pacific Coast. 

McClellan's Art Anatomy 

Anatomy in Its Relation to Art. By George McClellan, M. D. , Professor 
of Anatomy, Pennsylvania Academy of the Fine Arts. Quarto volume, 9 by 
\i% inches, with 338 original drawings and photographs, and 260 pages of 
text. Dark blue vellum, $10.00 net ; Half Russia, $12.50 net. 



U SAUNDERS' BOOKS ON 



Haynes' Anatomy 

A Manual of Anatomy. By Irving S. Haynes, M.D., Professor of Prac- 
tical Anatomy, Cornell University Medical College. Octavo, 680 pages, 
with 42 diagrams and 134 full-page half-tones. Cloth, $2.50 net. 

" This book is the work of a practical instructor — one who knows by experience the require- 
ments of the average student, and is able to meet these requirements in a very satisfactory 
way." — The Medical Record, New York. 

American Pocket Dictionary ^S 

The American Pocket Medical Dictionary. Edited by W. A. Newman 
Dorland, A.M.,M.D., Assistant Obstetrician, Hospital of the University of 
Pennsylvania, etc. 598 pages. Full leather, limp, with gold edges, $1.00 
net; with patent thumb index, $1.25 net. 

" I am struck at once with admiration at the compact size and attractive exterior. I can recom- 
mend it to our students without reserve." — James W. Holland, M.D., Professor of Medical 
Chemistry and Toxicology, at the Jefferson Medical College, J-'imadelpliia. 

Barton and Wells' Medical Thesaurus 

A Thesaurus of Medical Words and Phrases. By Wilfred M. Barton, 
M. D., Assistant to Professor of Materia Medica and Therapeutics, and Lec- 
turer on Pharmacy, Georgetown University, Washington, D. C. ; and Walter 
A. Wells, M. D., Demonstrator of Laryngology, Georgetown University, 
Washington, D. C. i2mo of 534 pages. Flexible leather, $2.50 net ; with 
thumb index, $3.00 net. 

Stoney's Surgical Technic The New ($£%& 

Bacteriology and Surgical Technic for Nurses. By Emily A. M. Stoney, 

Superintendent at the Carney Hospital, South Boston, Mass. Revised by 
Frederic R. Griffith, M. D., Surgeon, of New York. i2mo, 300 pages, 
illustrated. $1.50 net. 

" These subjects are treated most accurately and up to date, without the superfluous reading 
which is so often employed. . . . Nurses will find this book of the greatest value."— 
Trained Nurse and Hospital Review. 

Grant on Face, Mouth, and Jaws 

A Text=Book of the Surgical Principles and Surgical Diseases of the 
Face, Mouth, and Jaws. For Dental Students. By H. Horace Grant, 
A.M., M.D., Professor of Surgery and of Clinical Surgery, Hospital College 
of Medicine. Octavo of 231 pages, with 68 illustrations. Cloth, $2.50 net. 

" The language of the book is simple and clear. . . . We recommend the work to those for 
whom it is intended."— Philadelphia Medical Journal. 



SURGERY AND ANATOMY.* 15 



American Illustrated Dictionary The New <$?,££ 

The American Illustrated Medical Dictionary. With tables 
of Arteries, Muscles, Nerves, Veins, etc. ; of Bacilli, Bacteria, etc. ; 
Eponymic Tables of Diseases, Operations, Stains, Tests, etc. By W. A. 
Newman Borland, M.D. Large octavo, 876 pages. Flexible leather, 
$4.50 net; with thumb index, $5.00 net. 

Howard A. Kelly, M.D., Professor of Gynecology , Johns Hopkins University, Baltimore. 

"Dr. Dorland's dictionary is admirable. It is so well gotten up and of such conr 
venient size. No errors have been found in my use of it." 

Golebiewski and Bailey's Accident Diseases 

Atlas and Epitome of Diseases Caused by Accidents. By Dr. 

Ed. Golebiewski, of Berlin. Edited, with additions, by Pearce Bailey, 
M.D. Consulting Neurologist to St. Luke's Hospital, New York City. 
With 71 colored figures on 40 plates, 143 text-cuts, and 549 pages of 
text. Cloth, $4.00 net. In Saunders'' Hand- Atlas Series. 

Helferich and Bloodgood on Fractures 

Atlas and Epitome of Traumatic Fractures and Dislocations 

By Prof. Dr. H. Helferich, of Greifswald, Prussia. Edited, with ad- 
ditions, by Joseph C. Bloodgood, M. D., Associate in Surgery, Johns 
Hopkins University, Baltimore. 216 colored figures on 64 lithographic 
plates, 190 text-cuts, and 353 pages of text. Cloth, $3.00 net. In Saun- 
ders' Atlas Series. 

Sultan and Coley on Abdominal Hernias 

Atlas and Epitome of Abdominal Hernias. By Pr. Dr. G. Sul- 
tan, of Gottingen. Edited, with additions, by Wm. B. Coley, M. D., 
Clinical Lecturer and Instructor in Surgery, Columbia University, New 
York. 119 illustrations, 36 in colors, and 277 pages of text. Cloth, 
$3.00 net. In Saunders' Hand- Atlas Series. 

Warren's Surgical Pathology | e d ^ 

Surgical Pathology and Therapeutics. By J. Collins Warren, 
M.D., LL.D.,.F.R.C.S. (Hon.), Professor of Surgery, Harvard Medical 
School. Octavo, 873 pages ; 136 illustrations, 33 in colors. Cloth, 
$5.00 net; Half Morocco, $6.50 net. 

Zuckerkandl and DaCosta's Surgery lawon 

Atlas and Epitome of Operative Surgery. By Dr. O. Zucker- 
kandl, of Vienna. Edited, with additions, by J. Chalmers DaCosta, 
M. D., Professor of Surgery and Clinical Surgery, Jefferson Medical Col- 
lege, Phila. 40 colored plates, 278 text-cuts, and 410 pages of text. 
Cloth, $3.50 net. In Saunders' Atlas Series. 



16 SURGER Y AND ANA TOMY 



Moore's Orthopedic Surgery 

A Manual of Orthopedic Surgery. By James E. Moore, M.D., Professor 
of Clinical Surgery, University of Minnesota, College of Medicine and Surgery. 
Octavo of 356 pages, handsomely illustrated. Cloth, $2.50 net. 

"The book is eminently practical. It is a safe guide in the understanding and treatment of 
•rthopedic cases. Should be owned by every surgeon and practitioner."— Annals of Surgery. 

Fowler's Operating Room New (2d) Edition 

The Operating Room and the Patient, By Russell S. Fowler, M. D., 

Surgeon to the German Hospital, Brooklyn, New York. Octavo of 284 

pages, illustrated. Cloth, $2.00 net. 

Dr. Fowler has written his book for surgeons, nurses assisting at an operation, internes, 
and all others whose duties bring them into the operating room. It contains explicit 
directions for the preparation of material, instruments needed, position of patient, etc., 
all beautifully illustrated. 

Nancrede's Principles of Surgery New (2d) Edition 

Lectures on the Principles of Surgery. By Chas. B. Nancrede, M.D., 
LL.D., Professor of Surgery and of Clinical Surgery, University of Michigan, 
Ann Arbor. Octavo, 407 pages, illustrated. Cloth, $2.50 net. 

" We can strongly recommend this book to all students and those who would see something 
of the scientific foundation upon which the art of surgery is built."— Quarterly Medical Journal, 
Sheffield, England. 

Nancrede's Essentials of Anatomy. Seventh Edition 

Essentials of Anatomy, including the Anatomy of the Viscera. By Chas. 
B. Nancrede, M.D., Professor of Surgery and of Clinical Surgery, University 
of Michigan, Ann Arbor. Crown octavo, 388 pages ; 180 cuts. With an 
Appendix containing over 60 illustrations of the osteology of the body. Based 
on Gray 's Anatomy. Cloth, $1. 00 net. In Saunders Question Compends. 

" The questions have been wisely selected, and the answers accurately and concisely given." — 
University Medical Magazine. 

Martin's Essentials of Surgery. Seve RlviSd tioa 

Essentials of Surgery. Containing also Venereal Diseases, Surgical Land- 
marks, Minor and Operative Surgery, and a complete description, with illus- 
trations, of the Handkerchief and Roller Bandages. By Edward Martin, 
A.M., M.D., Professor of Clinical Surgery, University of Pennsylvania, etc. 
Crown octavo, 338 pages, illustrated. With an Appendix on Antiseptic Sur- 
gery, etc. Cloth, $i.on net. In Saunders Question Compends. 

"Written to assist the student, it will be A undoubted value to the practitioner, containing as it 
does the essence of surgical work." — Boston Medical and Surgical Journal. 

Martin's Essentials of Minor Surgery, Band- 
aging, and Venereal Diseases. Sec °Edi^ n Vised 

Essentials of Minor Surgery, Bandaging, and Venereal Diseases. By 

Edward Martin, A.M., M.D., Professor of Clinical Surgery, University of 
Pennsylvania, etc. Crown octavo, 166 pages, with 78 illustrations. 

Cloth, $1.00 net. In Saunders 1 Question Compends. 

"The best condensation of the subjects of which it treats yet placed before the profession,"— 

The Medical News, Philadelphia. 



IIOV 13 W* 



6061 ' St A ! 



i«J U-»- 












»o< 









nTtltiTT 



LIBRARY OF CONGRESS 






l!'M| 



r i'' 

V T 

1 1 

E Jjj 


I'i') ll i ii 1 III liii"' H 'lii' 1 

1 .ii' j*ill'i !'■ iii llrli- ' P'li! i ! I'll 1 ! 'Ii ' 1 hi! 

I li'llilit! lii'!! ''I'lri Ii iii!' illil I'tli'JIli! ill! 
H i! 1 1 ' '!!'' iilil 

1 U H 'I'm i l ! 'i '< ' il ill' ' ll 1 Ii Ii liii 

[ i '!|{ ii(Mi,i' ' '(''[I jj ' ' ijllii'iii llliiill 






1 : 



i'i! 



1 I 



I 



029 827 907 1 



Hit Illil 



■ 

l|!jli!|j I 

ii'iiliiiiiiii 



fill 

iii'! 
i 



li ! I 



'1 

III 


.>:>' 









i 



'I ! 

■ 

III! 

I ill 



1 i 



I 






""•' * 



hi 






I |l '! i ' 



'I " 



I I IHllll 



I 



I III! 



I 

1 






mSflm 



dfflP 






i 



v.iti 'in '.UUlt 'I l HIU I1IUU 



